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CN110621670B - Benzazepine analogues as inhibitors of Bruton's tyrosine kinase - Google Patents

Benzazepine analogues as inhibitors of Bruton's tyrosine kinase Download PDF

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CN110621670B
CN110621670B CN201880031744.6A CN201880031744A CN110621670B CN 110621670 B CN110621670 B CN 110621670B CN 201880031744 A CN201880031744 A CN 201880031744A CN 110621670 B CN110621670 B CN 110621670B
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tetrahydro
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pyrazol
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B.T.霍普金斯
B.马
R.普林斯
I.马克斯
J.P.莱西卡托斯
F.郑
M.彼得森
D.B.佩兴斯
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Bojian Massachusetts Co ltd
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Abstract

Provided are compounds of formula (I) or pharmaceutically acceptable salts thereof, and methods of producing the same, as well as compounds of formula (I) for use in the treatment of diseases responsive to inhibition of Bruton's tyrosine.

Description

作为布鲁顿氏酪氨酸激酶的抑制剂的苯并氮杂卓类似物Benzazepine analogs as inhibitors of Bruton's tyrosine kinase

相关申请Related Applications

本申请根据35U.S.C.§119(e)要求2017年4月14日提交的美国临时申请第62/485,745号的申请日的权益，所述临时申请的全部内容以引用的方式并入本文。This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 62/485,745, filed on April 14, 2017, the entire contents of which are incorporated herein by reference.

背景技术Background Art

提供某些抑制布鲁顿氏酪氨酸激酶(Btk)的药剂和制备并使用此类药剂的方法。Certain agents that inhibit Bruton's tyrosine kinase (Btk) and methods of making and using such agents are provided.

技术领域Technical Field

蛋白激酶为由多于500种蛋白质组成的大型多基因家族，所述蛋白质在肿瘤学、神经学和免疫学的许多人类疾病的发展和治疗中起关键作用。Tec激酶为由五个成员(Tec(肝细胞癌中表达的酪氨酸激酶)、Btk(布鲁顿氏酪氨酸激酶)、Itk(介白素-2(IL-2)-可诱导T细胞激酶；也称为Emt或Tsk)、Rlk(静息淋巴细胞激酶；也称为Txk)和Bmx(X染色体上的骨髓酪氨酸激酶基因；也称为Etk))组成的非受体酪氨酸激酶，并且主要表达于造血细胞中，但是在内皮细胞和干细胞中检测到Bmx和Tec的表达。Tec激酶(Itk、Rlk和Tec)表达于T细胞中，并且所有激酶均在T细胞受体(TCR)下游活化。Btk为参与调控B细胞活化、增殖和分化的B细胞受体(BCR)信号传导的下游介质。更确切地说，Btk含有结合(3,4,5)-三磷酸磷脂酰肌醇(PIP3)的PH结构域。PIP3结合诱导Btk将磷脂酶C(PLCy)磷酸化，其继而将PIP2水解以产生两种使蛋白激酶PKC活化的二级信使三磷酸肌醇(IP3)和二酰甘油(DAG)，所述蛋白激酶PKC然后诱导另外的B细胞信号传导。使Btk酶活性失效的突变导致XLA综合征(X连接的无γ球蛋白血症)，其为原发性免疫缺乏。考虑到Tec激酶在B细胞和T细胞中起到的关键作用，Tec激酶为自身免疫性病症的感兴趣的目标。Protein kinases are a large multigene family consisting of more than 500 proteins that play a key role in the development and treatment of many human diseases in oncology, neurology and immunology. Tec kinases are non-receptor tyrosine kinases consisting of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk) and Bmx (myeloid tyrosine kinase gene on chromosome X; also known as Etk)) and are mainly expressed in hematopoietic cells, but expression of Bmx and Tec is detected in endothelial cells and stem cells. Tec kinases (Itk, Rlk and Tec) are expressed in T cells, and all kinases are activated downstream of the T cell receptor (TCR). Btk is a downstream mediator of B cell receptor (BCR) signaling involved in regulating B cell activation, proliferation and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which in turn hydrolyzes PIP2 to produce two secondary messengers inositol triphosphate (IP3) and diacylglycerol (DAG) that activate protein kinase PKC, which then induces additional B cell signaling. Mutations that disable Btk enzymatic activity lead to XLA syndrome (X-linked agammaglobulinemia), which is a primary immune deficiency. Given the key role played by Tec kinases in B cells and T cells, Tec kinases are interesting targets for autoimmune disorders.

因此，本领域中存在对有效Btk抑制剂的极大需求。Therefore, there is a great need in the art for effective Btk inhibitors.

发明内容Summary of the invention

本发明的第一实施方案为式(I)化合物：The first embodiment of the present invention is a compound of formula (I):

或药学上可接受的盐，其中：or a pharmaceutically acceptable salt, wherein:

A环为含有3个独立地选自N、O和S的杂原子的5元单环杂芳基，其中所述5元单环杂芳基任选地被一个或多个R1取代；Ring A is a 5-membered monocyclic heteroaryl containing 3 heteroatoms independently selected from N, O and S, wherein the 5-membered monocyclic heteroaryl is optionally substituted with one or more R 1 ;

Q1、Q2和Q3各独立地选自O、N(R2)和CH-R3，其中Q1、Q2和Q3的至少两者为C-R3；Q 1 , Q 2 and Q 3 are each independently selected from O, N(R 2 ) and CH-R 3 , wherein at least two of Q 1 , Q 2 and Q 3 are CR 3 ;

W选自CH和N；W is selected from CH and N;

Y选自CH和N；Y is selected from CH and N;

R1在每次出现时独立地选自C1-6烷基和3至5元碳环基，其中所述C1-6烷基和3至5元碳环基任选地被一个或多个R10取代；R 1 is independently selected at each occurrence from C 1-6 alkyl and 3 to 5 membered carbocyclyl, wherein said C 1-6 alkyl and 3 to 5 membered carbocyclyl are optionally substituted with one or more R 10 ;

R10在每次出现时独立地选自卤基、-CN、C1-6烷基和3至5元碳环基；R 10 at each occurrence is independently selected from halo, -CN, C 1-6 alkyl, and 3 to 5 membered carbocyclyl;

R2选自H、C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基、4至6元单环杂环基、-CN、-C(O)R2a、-C(O)2R2a、-C(O)N(R2a)2、-S(O)2R2a和-S(O)2N(R2a)2，其中所述C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基任选地被一个或多个R20取代；R 2 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, 4 to 6 membered monocyclic heterocyclyl, -CN, -C(O)R 2a , -C(O) 2 R 2a , -C(O)N(R 2a ) 2 , -S(O) 2 R 2a and -S(O) 2 N(R 2a ) 2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl and 4 to 6 membered monocyclic heterocyclyl are optionally substituted with one or more R 20 ;

R2a在每次出现时独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基，其中所述C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基在每次出现时任选且独立地被一个或多个R20取代；R 2a is independently selected at each occurrence from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, and 4 to 6 membered monocyclic heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, and 4 to 6 membered monocyclic heterocyclyl are optionally and independently substituted with one or more R 20 at each occurrence;

R20在每次出现时独立地选自C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基、4至6元单环杂环基、卤基、-CN、-C(O)R20a、-C(O)2R20a、-C(O)N(R20a)2、-N(R20a)2、-N(R20a)C(O)R20a、-N(R20a)C(O)2R20a、-N(R20a)C(O)N(R20a)2、-N(R20a)S(O)2R20a、-OR20a、-OC(O)R20a、-OC(O)N(R20a)2、-SR20a、-S(O)R20a、-S(O)2R20a、-S(O)N(R20a)2和-S(O)2N(R20a)2； R20 is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, -CN, -C(O ) R20a , -C(O) 2R20a , -C(O)N( R20a ) 2 , -N( R20a ) 2 , -N( R20a )C(O) R20a , -N( R20a )C(O) 2R20a , -N( R20a )C(O)2N( R20a ) 2 , -N (R20a)S(O)2R20a , -OR20a , -OC(O) R20a , -OC(O)N( R20a ) 2 , -SR 20a , -S(O)R 20a , -S(O) 2 R 20a , -S(O)N(R 20a ) 2 and -S(O) 2 N(R 20a ) 2 ;

R20a在每次出现时独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基；R 20a at each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, and 4 to 6 membered monocyclic heterocyclyl;

R3选自H、C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基、4至6元单环杂环基、卤基、-CN、-C(O)R3a、-C(O)2R3a、-C(O)N(R3a)2、-N(R3a)2、-N(R3a)C(O)R3a、-N(R3a)C(O)2R3a、-N(R3a)C(O)N(R3a)2、-N(R3a)S(O)2R3a、-OR3a、-OC(O)R3a、-OC(O)N(R3a)2、-SR3a、-S(O)R3a、-S(O)2R3a、-S(O)N(R3a)2和-S(O)2N(R3a)2，其中所述C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基任选地被一个或多个R30取代； R3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, -CN, -C(O) R3a , -C(O) 2R3a , -C(O)N( R3a ) 2 , -N( R3a ) 2 , -N( R3a )C( O ) R3a , -N( R3a )C(O) 2R3a , -N( R3a )C(O)N( R3a ) 2 , -N( R3a ) S (O) 2R3a , -OR3a , -OC(O) R3a , -OC(O)N( R3a ) 2 , -SR3a , -S(O) R3a , -S(O) 2 R 3a , -S(O) 2 (R 3a ) 2 and -S(O) 2 N (R 3a ) 2 , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl and 4 to 6 membered monocyclic heterocyclyl are optionally substituted with one or more R 30 ;

R3a在每次出现时独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基，其中所述C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基在每次出现时任选且独立地被一个或多个R30取代；R 3a is independently selected at each occurrence from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, and 4 to 6 membered monocyclic heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, and 4 to 6 membered monocyclic heterocyclyl are optionally and independently substituted at each occurrence with one or more R 30 ;

R30在每次出现时独立地选自C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基、4至6元单环杂环基、卤基、-CN、-C(O)R30a、-C(O)2R30a、-C(O)N(R30a)2、-N(R30a)2、-N(R30a)C(O)R30a、-N(R30a)C(O)2R30a、-N(R30a)C(O)N(R30a)2、-N(R30a)S(O)2R30a、-OR30a、-OC(O)R30a、-OC(O)N(R30a)2、-SR30a、-S(O)R30a、-S(O)2R30a、-S(O)N(R30a)2和-S(O)2N(R30a)2； R30 is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, -CN, -C(O ) R30a , -C(O) 2R30a , -C(O)N( R30a ) 2 , -N( R30a ) 2 , -N( R30a )C(O) R30a , -N( R30a )C(O) 2R30a , -N( R30a )C(O) N ( R30a ) 2 , -N ( R30a )S(O) 2R30a , -OR30a , -OC(O) R30a , -OC(O)N( R30a ) 2 , -SR 30a , -S(O)R 30a , -S(O) 2 R 30a , -S(O)N(R 30a ) 2 and -S(O) 2 N(R 30a ) 2 ;

R30a在每次出现时独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、4至6元单环碳环基和4至6元单环杂环基；R 30a at each occurrence is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 4 to 6 membered monocyclic carbocyclyl, and 4 to 6 membered monocyclic heterocyclyl;

R4选自H和C1-6烷基，其中所述C1-6烷基任选地被一个或多个卤基取代；R 4 is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups;

R5选自H和C1-6烷基，其中所述C1-6烷基任选地被一个或多个卤基取代；R 5 is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups;

R6选自H和C1-6烷基，其中所述C1-6烷基任选地被一个或多个卤基取代；R 6 is selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more halo groups;

或R5和R6连同其所连接的原子一起形成含有一个或两个选自O、N和S的杂原子的环，其中所述环任选地被一个或多个R50取代；并且or R 5 and R 6 together with the atoms to which they are attached form a ring containing one or two heteroatoms selected from O, N and S, wherein the ring is optionally substituted with one or more R 50 ; and

R50为C1-6-烷基。 R50 is C1-6- alkyl.

本发明还提供一种药物组合物，其包含至少一种本文所述的化合物或其药学上可接受的盐和至少一种药学上可接受的赋形剂。The present invention also provides a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

在一个实施方案中，本发明为一种治疗受试者的对Btk的抑制有反应的病症的方法，其包括向所述受试者施用有效量的至少一种本文所述的化合物或其药学上可接受的盐。In one embodiment, the invention is a method of treating a condition responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

本发明还包括至少一种本文所述的化合物或其药学上可接受的盐用于制备用于治疗对Btk的抑制有反应的病症的药物的用途。还提供一种本文所述的化合物或其药学上可接受的盐，其用于治疗对Btk的抑制有反应的病症。The present invention also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a condition responsive to inhibition of Btk. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof for use in treating a condition responsive to inhibition of Btk.

其他特征或优势将根据对若干实施方案的以下详述以及根据随附权利要求书而显而易知。Other features and advantages will be apparent from the following detailed description of several embodiments and from the appended claims.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1示出(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形A的粉末X射线衍射(PXRD)图。FIG1 shows (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Powder X-ray diffraction (PXRD) pattern of crystalline form A of 1,2,3-triazole-4-carboxamide.

图2示出(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形A的差示扫描量热法(DSC)和热重分析(TGA)曲线。FIG. 2 shows (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of Form A of 1H-5-yl)-1H-1,2,3-triazole-4-carboxamide.

图3A示出(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形A的溶液13C NMR谱。图3B示出晶形A的固态13NMR谱。FIG3A shows (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Solution 13 C NMR spectrum of Form A of 1H-5-yl)-1H-1,2,3-triazole-4-carboxamide. FIG3B shows the solid-state 13 NMR spectrum of Form A.

图4示出(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形G的粉末X射线衍射(PXRD)图。FIG. 4 shows (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Powder X-ray diffraction (PXRD) pattern of Form G of 1H-1,2,3-triazole-4-carboxamide.

图5示出(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形G的差示扫描量热法(DSC)和热重分析(TGA)曲线。FIG. 5 shows (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of Form G of 1H-5-yl)-1H-1,2,3-triazole-4-carboxamide.

图6A示出(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形G的溶液13C NMR谱。图6B示出晶形G的固态13NMR谱。FIG6A shows (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine 6B shows the solid - state 13 NMR spectrum of Form G.

具体实施方式DETAILED DESCRIPTION

如本文所述的化合物或其药学上可接受的盐可具有作为Btk调节剂的活性。具体而言，如本文所述的化合物或其药学上可接受的盐可为Btk抑制剂。The compounds as described herein, or pharmaceutically acceptable salts thereof, may have activity as Btk modulators. Specifically, the compounds as described herein, or pharmaceutically acceptable salts thereof, may be Btk inhibitors.

在本发明的第二实施方案中，所述化合物由式(I)或其药学上可接受的盐表示，其中Q1、Q2和Q3各自独立地为CH-R3，并且其他变项的定义为如第一实施方案中所定义。In a second embodiment of the invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q1 , Q2 and Q3 are each independently CH- R3 , and the other variables are defined as in the first embodiment.

在本发明的第三实施方案中，所述化合物由式(I)或其药学上可接受的盐表示，其中Q2为N(R2)，Q1和Q3各自独立地为CH-R3，并且其他变项的定义为如第一实施方案中所定义。In a third embodiment of the invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q2 is N( R2 ), Q1 and Q3 are each independently CH- R3 , and the other variables are defined as in the first embodiment.

在本发明的第四实施方案中，所述化合物由式(I)或其药学上可接受的盐表示，其中Q3为N(R2)，Q1和Q2各自独立地为CH-R3，并且其他变项的定义为如第一实施方案中所定义。In a fourth embodiment of the invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q3 is N( R2 ), Q1 and Q2 are each independently CH- R3 , and the other variables are defined as in the first embodiment.

在本发明的第五实施方案中，所述化合物由式(I)或其药学上可接受的盐表示，其中Q1为O，Q2和Q3各自独立地为CH-R3，并且其他变项的定义为如第一实施方案中所定义。In a fifth embodiment of the invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Q1 is O, Q2 and Q3 are each independently CH- R3 , and the other variables are defined as in the first embodiment.

在本发明的第六实施方案中，所述化合物由式(I)或其药学上可接受的盐表示，W为CH；并且其他变项的定义为如第一、第二、第三、第四或第五实施方案中所定义。In a sixth embodiment of the invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, W is CH; and the other variables are defined as in the first, second, third, fourth or fifth embodiment.

在本发明的第七实施方案中，所述化合物由式(I)或其药学上可接受的盐表示，其中Y为N；并且其他变项的定义为如第一、第二、第三、第四、第五或第六实施方案中所定义。In a seventh embodiment of the invention, the compound is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is N; and the other variables are defined as in the first, second, third, fourth, fifth or sixth embodiment.

在本发明的第八实施方案中，本发明的化合物由下式中的任一者或其药学上可接受的盐表示：In an eighth embodiment of the present invention, the compound of the present invention is represented by any one of the following formulae or a pharmaceutically acceptable salt thereof:

或 or

并且其他变项的定义为如第一实施方案中所定义。And the definitions of other variables are as defined in the first embodiment.

在本发明的第九实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中A环选自1,2,3-噁二唑、1,3,4-噁二唑、1,2,4-噁二唑、1,2,3-噻二唑、1,3,4-噻二唑、1,2,4-噻二唑、1,2,3-三唑和1,2,4-三唑，其各自任选地被一个或两个R1取代；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所定义。In a ninth embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole and 1,2,4-triazole, each of which is optionally substituted with one or two R 1 ; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

在本发明的第十实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中A环由下式之一表示：In a tenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein Ring A is represented by one of the following formulae:

或 or

并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七或第八实施方案中所定义。And the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

在本发明的第十一实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In an eleventh embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein:

R1在每次出现时独立地为C1-6烷基或C3-5环烷基；其中所述C1-6烷基和C3-5环烷基任选地被一至三个R10取代；R 1 is independently C 1-6 alkyl or C 3-5 cycloalkyl at each occurrence; wherein said C 1-6 alkyl and C 3-5 cycloalkyl are optionally substituted by one to three R 10 ;

R10在每次出现时独立地选自卤基、-CN和C1-6烷基；R 10 at each occurrence is independently selected from halo, -CN and C 1-6 alkyl;

并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九或第十实施方案中所定义。And the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment.

在本发明的第十二实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In a twelfth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein:

R1在每次出现时独立地为C1-4烷基、环丙基或环丁基；其中所述C1-4烷基、环丙基和环丁基任选地被一至三个R10取代；R 1 is independently, at each occurrence, C 1-4 alkyl, cyclopropyl or cyclobutyl; wherein said C 1-4 alkyl, cyclopropyl and cyclobutyl are optionally substituted with one to three R 10 ;

R10在每次出现时独立地选自卤基、-CN和C1-3烷基；R 10 at each occurrence is independently selected from halo, -CN and C 1-3 alkyl;

并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九或第十实施方案中所定义。And the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment.

在本发明的第十三实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In a thirteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein:

R1在每次出现时独立地选自-C(CH3)3、-CH(CH3)2、-C(CH3)2CHF2、-C(CH3)2CF3、-C(CH3)2CH2F、-C(CH3)2CN、1-甲基环丙基、环丁基和3,3-二氟环丁基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九或第十实施方案中所定义。 R1 at each occurrence is independently selected from -C( CH3 ) 3 , -CH ( CH3 ) 2 , -C( CH3 ) 2CHF2 , -C( CH3 ) 2CF3 , -C(CH3)2CH2F, -C( CH3 ) 2CN , 1-methylcyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl; and the other variables are defined as in the first, second, third, fourth, fifth , sixth, seventh, eighth, ninth or tenth embodiment.

在本发明的第十四实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R1为-C(CH3)3；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九或第十实施方案中所定义。In a fourteenth embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R 1 is -C(CH 3 ) 3 ; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment.

在本发明的第十五实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In a fifteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein:

R2选自H、C1-6烷基、C4-6环烷基、饱和4至6元单环杂环基、-C(O)R2a、-C(O)2R2a和-S(O)2R2a，其中所述C1-6烷基、C4-6环烷基和4至6元单环杂环基任选地被一至三个R20取代；R 2 is selected from H, C 1-6 alkyl, C 4-6 cycloalkyl, saturated 4 to 6-membered monocyclic heterocyclyl, -C(O)R 2a , -C(O) 2 R 2a and -S(O) 2 R 2a , wherein said C 1-6 alkyl, C 4-6 cycloalkyl and 4 to 6-membered monocyclic heterocyclyl are optionally substituted with one to three R 20 ;

R2a在每次出现时独立地选自H、C1-6烷基、C4-6烷基和饱和4至6元单环杂环基，其中所述C1-6烷基、4至6元单环碳环基和饱和4至6元单环杂环基在每次出现时任选且独立地被一个或多个R20取代；R 2a is independently selected at each occurrence from H, C 1-6 alkyl, C 4-6 alkyl, and saturated 4 to 6 membered monocyclic heterocyclyl, wherein said C 1-6 alkyl, 4 to 6 membered monocyclic carbocyclyl, and saturated 4 to 6 membered monocyclic heterocyclyl are optionally and independently substituted at each occurrence with one or more R 20 ;

R20在每次出现时独立地选自C1-6烷基、C4-6-环烷基、饱和4至6元单环杂环基、卤基、-CN、-N(R20a)2和-OR20a；R 20 is independently selected at each occurrence from C 1-6 alkyl, C 4-6- cycloalkyl, saturated 4 to 6-membered monocyclic heterocyclyl, halo, -CN, -N(R 20a ) 2 and -OR 20a ;

R20a在每次出现时独立地为H或C1-6烷基；R 20a at each occurrence is independently H or C 1-6 alkyl;

并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三或第十四实施方案中所定义。and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment.

在第十六实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In a sixteenth embodiment, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein:

R2选自H，C1-6烷基，选自环丁基、环戊基和环己基的C4-6环烷基，选自氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、硫杂环戊烷基(thiolanyl)、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧环戊烷基(dioxolanyl)、二硫环戊烷基、氧硫环戊烷基、哌啶基、四氢吡喃基、硫杂环己烷基(thianyl)、哌嗪基、吗啉基、硫吗啉基和二噁烷基的饱和4至6元单环杂环基，-C(O)R2a，-C(O)2R2a和-S(O)2R2a，其中所述C1-6烷基、C4-6环烷基和饱和4至6元单环杂环基任选地被一至三个R20取代； R is selected from H, Ci -6 alkyl, a C4-6 cycloalkyl selected from cyclobutyl, cyclopentyl and cyclohexyl, a saturated 4 to 6 membered monocyclic heterocyclyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl and dioxanyl, -C(O)R2a, -C(O)2R2a and -S (O) 2R2a , wherein said Ci -6 alkyl, C4-6 cycloalkyl and saturated 4 to 6 membered monocyclic heterocyclyl are optionally substituted with one to three R20 ;

R2a为任选且独立地被一至三个R20取代的C1-6烷基；R 2a is C 1-6 alkyl optionally and independently substituted by one to three R 20 ;

R20在每次出现时独立地选自C1-3烷基、环丙基、环丁基、环戊基、环己基、卤基、-N(R20a)2和-OR20a；R 20 is independently selected at each occurrence from C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, -N(R 20a ) 2 and -OR 20a ;

R20a在每次出现时独立地为H或C1-3烷基；并且R 20a at each occurrence is independently H or C 1-3 alkyl; and

其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四或第十五实施方案中所定义。The other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

在本发明的第十七实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In a seventeenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein:

R2选自H、C1-6烷基、环丁基、环戊基和环己基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、-C(O)R2a、-C(O)2R2a和-S(O)2R2a，其中所述C1-6烷基、环丁基、环戊基和环己基、氧杂环丁烷基、四氢呋喃基和四氢吡喃基任选地被一至三个R20取代；R 2 is selected from H, C 1-6 alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -C(O)R 2a , -C(O) 2 R 2a and -S(O) 2 R 2a , wherein said C 1-6 alkyl, cyclobutyl, cyclopentyl and cyclohexyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl are optionally substituted with one to three R 20 ;

R2a为任选地被一个R20取代的C1-6烷基；R 2a is C 1-6 alkyl optionally substituted by one R 20 ;

R20在每次出现时独立地选自C1-3烷基、环丙基、环丁基、环戊基、环己基、卤基、-N(R20a)2和-OR20a；R 20 is independently selected at each occurrence from C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, -N(R 20a ) 2 and -OR 20a ;

R20a在每次出现时独立地为H或甲基；R 20a at each occurrence is independently H or methyl;

其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四或第十五实施方案中所定义。The other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

在本发明的第十八实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R2选自-H、-SO2CH3、-C(＝O)OC(CH3)3、-C(＝O)CH2N(CH3)2、-CH3、-CH2CH3、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH(CH3)OH、-CH2C(CH3)2OH、-CH2CH2CH2OH、-CH2CHF2、-CH2CF3、和并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四或第十五实施方案中所定义。In an eighteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from -H, -SO 2 CH 3 , -C(=O)OC(CH 3 ) 3 , -C(=O)CH 2 N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 3 , -CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 OH, -CH 2 CH 2 CH 2 OH, -CH 2 CHF 2 , -CH 2 CF 3 , and and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

在本发明的第十九实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R2选自-CH2CHF2、-CH2CF3、-CH2CH2OH、-CH2CH(CH3)OH、-CH2CH2OCH3、和 In a nineteenth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from -CH 2 CHF 2 , -CH 2 CF 3 , -CH 2 CH 2 OH, -CH 2 CH(CH 3 )OH, -CH 2 CH 2 OCH 3 , and

在本发明的第二十实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中：In a twentieth embodiment of the present invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein:

R3选自H、C1-6烷基、C4-6环烷基、饱和4至6元单环杂环基、卤基、-OR3a、-OC(O)R3a、-OC(O)N(R3a)2和-SR3a，其中所述C1-6烷基、C4-6环烷基和饱和4至6元单环杂环基任选地被一至三个R30取代；R 3 is selected from H, C 1-6 alkyl, C 4-6 cycloalkyl, saturated 4 to 6-membered monocyclic heterocyclyl, halogen, -OR 3a , -OC(O)R 3a , -OC(O)N(R 3a ) 2 , and -SR 3a , wherein said C 1-6 alkyl, C 4-6 cycloalkyl, and saturated 4 to 6-membered monocyclic heterocyclyl are optionally substituted with one to three R 30 ;

R3a在每次出现时独立地为H或C1-6烷基，其中所述C1-6烷基在每次出现时任选且独立地被一个R30取代；R 3a at each occurrence is independently H or C 1-6 alkyl, wherein said C 1-6 alkyl at each occurrence is optionally and independently substituted with one R 30 ;

R30在每次出现时独立地选自C1-6烷基；R 30 at each occurrence is independently selected from C 1-6 alkyl;

并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八或第十九实施方案中所定义。and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth or nineteenth embodiment.

在本发明的第二十一实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R3选自H、卤基和-OR3a；R3a独立地为H或C1-3烷基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八或第十九实施方案中所定义。In a twenty-first embodiment of the invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, halo and -OR 3a ; R 3a is independently H or C 1-3 alkyl; and the other variables are defined as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth or nineteenth embodiment.

在本发明的第二十二实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R3选自H、-F和-OH；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八或第十九实施方案中所定义。In a twenty-second embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, -F and -OH; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth or nineteenth embodiment.

在本发明的第二十三实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R4为H或任选地被一至三个氟取代的C1-3烷基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一或第二十二实施方案中所定义。In a twenty-third embodiment of the invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R4 is H or C1-3 alkyl optionally substituted with one to three fluorines; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment.

在本发明的第二十四实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R4为H或甲基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一或第二十二实施方案中所定义。In a twenty-fourth embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R is H or methyl; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment.

在本发明的第二十五实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R5为H或任选地被一至三个氟取代的C1-3烷基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三或第二十四实施方案中所定义。In a twenty-fifth embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R5 is H or C1-3 alkyl optionally substituted with one to three fluorines; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment.

在本发明的第二十六实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R5为H、甲基、乙基或异丙基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三或第二十四实施方案中所定义。In a twenty-sixth embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV'), or (V'), or a pharmaceutically acceptable salt thereof, wherein R 5 is H, methyl, ethyl, or isopropyl; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.

在本发明的第二十七实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R6为H或任选地被一至三个氟取代的C1-3烷基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四、第二十五或第二十六实施方案中所定义。In a twenty-seventh embodiment of the invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R6 is H or C1-3 alkyl optionally substituted with one to three fluorines; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.

在本发明的第二十八实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R6为H、甲基或三氟甲基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三、第二十四实、第二十五或第二十六施例中所定义。In a twenty-eighth embodiment of the invention, the compound is represented by Formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R is H, methyl or trifluoromethyl; and the other variables are defined as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth or twenty-sixth embodiment.

在本发明的第二十九实施方案中，所述化合物由式(I)、(II)、(III)、(IV)、(V)、(II')、(III')、(IV')或(V')或其药学上可接受的盐表示，其中R5和R6连同其所连接的原子一起形成含有一个或两个选自O、N和S的杂原子的5至6元饱和杂环，其中所述环任选地被一个R50取代；R50为C1-3烷基；并且其他变项的定义为如第一、第二、第三、第四、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十七、第十八、第十九、第二十、第二十一、第二十二、第二十三或第二十四实施方案中所定义。在一个更具体实施方案中，所述5至6元饱和杂环为吡咯烷、哌嗪或N-甲基哌嗪。In a twenty-ninth embodiment of the invention, the compound is represented by formula (I), (II), (III), (IV), (V), (II'), (III'), (IV') or (V'), or a pharmaceutically acceptable salt thereof, wherein R and R together with the atoms to which they are attached form a 5- to 6-membered saturated heterocyclic ring containing one or two heteroatoms selected from O, N and S, wherein the ring is optionally substituted with one R ; R is C 1-3 alkyl; and the other variables are defined as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third or twenty-fourth embodiment. In a more specific embodiment, the 5- to 6-membered saturated heterocyclic ring is pyrrolidine, piperazine or N-methylpiperazine.

在本发明的第三十实施方案中，所述化合物由下式或其药学上可接受的盐表示：In the thirtieth embodiment of the present invention, the compound is represented by the following formula or a pharmaceutically acceptable salt thereof:

或 or

其中：in:

A环由下式之一表示：Ring A is represented by one of the following formulae:

或 or

R1为C1-6烷基； R1 is C1-6 alkyl;

R2为C1-6烷基、氧杂环丁烷基、四氢呋喃基或四氢吡喃基，其中所述C1-6烷基任选地被一至三个R20取代；R 2 is C 1-6 alkyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, wherein the C 1-6 alkyl is optionally substituted with one to three R 20 ;

R20在每次出现时独立地为卤基或-OR20a；R 20 at each occurrence is independently halo or -OR 20a ;

R20a为H或C1-3烷基；R 20a is H or C 1-3 alkyl;

R3为H；并且 R3 is H; and

R5为H或C1-3烷基。 R5 is H or C1-3 alkyl.

在本发明的第三十一实施方案中，所述化合物由式(IIA)、(IVA)、(VA)、(IIA')、(IVA')或(VA')或其药学上可接受的盐表示，其中R1为叔丁基；并且其他变项的定义为如第三十实施方案中所定义。In the thirty-first embodiment of the invention, the compound is represented by formula (IIA), (IVA), (VA), (IIA'), (IVA') or (VA'), or a pharmaceutically acceptable salt thereof, wherein R 1 is tert-butyl; and the other variables are defined as defined in the thirtieth embodiment.

在本发明的第三十二实施方案中，所述化合物由式(IIA)或(IIA')或其药学上可接受的盐表示，其中R2为-CH2CHF2、-CH2CF3、-CH2CH2OH、-CH2CH2OCH3或-CH2C(CH3)OH；并且其他变项的定义为如第三十或三十一实施方案中所定义。In the thirty-second embodiment of the present invention, the compound is represented by formula (IIA) or (IIA') or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH2CHF2 , -CH2CF3 , -CH2CH2OH , -CH2CH2OCH3 , or -CH2C ( CH3 ) OH ; and the other variables are defined as in the thirtieth or thirty-first embodiment.

在本发明的第三十三实施方案中，所述化合物由式(IVA)至(IVA')或其药学上可接受的盐表示，其中R3为H；并且其他变项的定义为如第三十或第三十一实施方案中所定义。In a thirty-third embodiment of the invention, the compound is represented by Formula (IVA) to (IVA') or a pharmaceutically acceptable salt thereof, wherein R 3 is H; and the other variables are defined as in the thirtieth or thirty-first embodiment.

在本发明的第三十四实施方案中，所述化合物由式(IIA)、(IVA)、(VA)、(IIA')、(IVA')或(VA')或其药学上可接受的盐表示，其中R5为甲基或异丙基；并且其他变项的定义为如第三十、第三十一、第三十二或第三十三实施方案中所定义。In a thirty-fourth embodiment of the invention, the compound is represented by Formula (IIA), (IVA), (VA), (IIA'), (IVA') or (VA'), or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl or isopropyl; and the other variables are defined as defined in the thirtieth, thirty-first, thirty-second or thirty-third embodiment.

在本发明的第三十五实施方案中，本发明的化合物选自：In a thirty-fifth embodiment of the present invention, the compound of the present invention is selected from:

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

(R)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-((S)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-((S)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-((S)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide

(S)-1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide

1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((5R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-((5R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(2-(2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((R)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((S)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-((S)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-((S)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-((S)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(2-(2,2-二氟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(2,2-二氟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2,2-二氟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

(R)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺、(R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

(S)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺、(S)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

3-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-5-甲酰胺、3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-5-carboxamide,

(R)-3-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-5-甲酰胺、(R)-3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-5-carboxamide,

(S)-3-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-5-甲酰胺、(S)-3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-5-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,2,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,2,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,2,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide,

1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(3-(2-羟乙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-Butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-(2-羟乙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-(2-羟乙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-Butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺(S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-((R)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-((R)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-Butyl)-N-((R)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-((S)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-Butyl)-N-((S)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-((S)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺5-(tert-butyl)-N-((S)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide

5-(叔丁基)-N-(3-(2-羟基-2-甲基丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-(2-羟基-2-甲基丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-(2-羟基-2-甲基丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(3-(2-hydroxy-2-methylpropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

1-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(3-甲基-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(3-甲基-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(3-甲基-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(3-(2-羟乙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(3-(2-羟乙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-Butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(3-(2-羟乙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(3-(2-hydroxyethyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide

5-(叔丁基)-N-(2-(2-(二甲基氨基)乙酰基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-(二甲基氨基)乙酰基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-(二甲基氨基)乙酰基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-Butyl)-N-(2-(2-(dimethylamino)acetyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1,1,1-三氟-2-甲基丙-2-基)-1,3,4-噁二唑-2-甲酰胺、N-(2-(2-Hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1,1,1-三氟-2-甲基丙-2-基)-1,3,4-噁二唑-2-甲酰胺、(R)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1,1,1-三氟-2-甲基丙-2-基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,

N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1,1,1-三氟-2-甲基丙-2-基)-1,3,4-噁二唑-2-甲酰胺、N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1,1,1-三氟-2-甲基丙-2-基)-1,3,4-噁二唑-2-甲酰胺、(R)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1,1,1-三氟-2-甲基丙-2-基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1,1-二氟-2-甲基丙-2-基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(1,1-difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(1,1-二氟-2-甲基丙-2-基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(1,1-二氟-2-甲基丙-2-基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1,1-二氟-2-甲基丙-2-基)-N-(2-(2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1,1-二氟-2-甲基丙-2-基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(1,1-二氟-2-甲基丙-2-基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(1,1-二氟-2-甲基丙-2-基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(1,1-二氟-2-甲基丙-2-基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(1,1-二氟-2-甲基丙-2-基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1-氟-2-甲基丙-2-基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(1-Fluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(1-氟-2-甲基丙-2-基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

(S)-5-(1-氟-2-甲基丙-2-基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(1-Fluoro-2-methylpropan-2-yl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1-氟-2-甲基丙-2-基)-N-(2-(2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(1-Fluoro-2-methylpropan-2-yl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(1-氟-2-甲基丙-2-基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(1-Fluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(1-氟-2-甲基丙-2-基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(1-氟-2-甲基丙-2-基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(1-fluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(1-氟-2-甲基丙-2-基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(1-Fluoro-2-methylpropan-2-yl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(1-氟-2-甲基丙-2-基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(1-Fluoro-2-methylpropan-2-yl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-环丁基-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-cyclobutyl-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-环丁基-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-Cyclobutyl-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-环丁基-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-Cyclobutyl-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(2-氰基丙-2-基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(2-cyanopropan-2-yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(2-氰基丙-2-基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(2-cyanopropan-2-yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(2-氰基丙-2-基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(2-cyanopropan-2-yl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(2-氰基丙-2-基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(2-cyanopropan-2-yl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(2-氰基丙-2-基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(2-cyanopropan-2-yl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(2-氰基丙-2-基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(2-cyanopropan-2-yl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

1-异丙基-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-Isopropyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-异丙基-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-Isopropyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-异丙基-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-Isopropyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-环丁基-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-Cyclobutyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-环丁基-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-Cyclobutyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-环丁基-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-Cyclobutyl-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

3-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-5-甲酰胺、3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-5-carboxamide,

(R)-3-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-5-甲酰胺、(R)-3-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-5-carboxamide,

(S)-3-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-5-甲酰胺、(S)-3-(tert-Butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-5-carboxamide,

1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(2-乙基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-乙基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-乙基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺1-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide

(R)-1-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(2-(2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺5-(tert-butyl)-N-(2-(2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide

5-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-乙基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-Butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-乙基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-乙基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-Butyl)-N-(2-ethyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-羟基-2-甲基丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-hydroxy-2-methylpropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-叔丁基-1,3,4-噁二唑-2-羧酸{(R)-2-(2-羟基-2-甲基-丙基)-8-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2,3,4,5-四氢-1H-2-苯并氮杂-5-基}-酰胺、5-tert-Butyl-1,3,4-oxadiazole-2-carboxylic acid {(R)-2-(2-hydroxy-2-methyl-propyl)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-2-benzazepine -5-yl}-amide,

(S)-5-(叔丁基)-N-(2-(2-羟基-2-甲基丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-hydroxy-2-methylpropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(3-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(3-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(3-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(S)-5-(tert-Butyl)-N-(2-(3-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide

N-(8-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺、N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(8-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺、(R)-N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,

(S)-N-(8-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(8-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

1-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、(R)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

(S)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

1-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

1-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

1-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-Butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-Butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(2-(环丙基甲基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(环丙基甲基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(环丙基甲基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(cyclopropylmethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1,3-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1,3-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

N-(2-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(叔丁基)-1,2,4-噁二唑-3-甲酰胺、N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide,

(R)-N-(2-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(叔丁基)-1,2,4-噁二唑-3-甲酰胺、(R)-N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide,

(S)-N-(2-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(叔丁基)-1,2,4-噁二唑-3-甲酰胺、(S)-N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((5-甲基-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-3-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

N-(2-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺、N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(2-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺、(R)-N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,

(S)-N-(2-(2-((1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(2-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide,

1-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-4-甲基-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-4H-1,2,4-三唑-3-甲酰胺、5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-4H-1,2,4-triazole-3-carboxamide,

(R)-5-(叔丁基)-4-甲基-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-4H-1,2,4-三唑-3-甲酰胺、(R)-5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-4H-1,2,4-triazole-3-carboxamide,

(S)-5-(叔丁基)-4-甲基-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-4H-1,2,4-三唑-3-甲酰胺、(S)-5-(tert-butyl)-4-methyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-4H-1,2,4-triazole-3-carboxamide,

2-异丙基-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-2H-1,2,3-三唑-4-甲酰胺、2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-2H-1,2,3-triazole-4-carboxamide,

(R)-2-异丙基-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-2H-1,2,3-三唑-4-甲酰胺、(R)-2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-2H-1,2,3-triazole-4-carboxamide,

(S)-2-异丙基-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-2H-1,2,3-三唑-4-甲酰胺、(S)-2-isopropyl-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-2H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((8S)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((8R)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((5R,8S)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((5R,8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((5S,8R)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((5S,8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((5R,8R)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((5R,8R)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-((5S,8S)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-((5S,8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

N-(8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺、N-(8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

N-((8S)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺、N-((8S)-8-fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide,

N-((8R)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺N-((8R)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

N-((5R,8S)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺N-((5R,8S)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

N-((5S,8R)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺N-((5S,8R)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

N-((5S,8S)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺N-((5S,8S)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

N-((5S,8R)-8-氟-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺N-((5S,8R)-8-Fluoro-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、(R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

(S)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-环丁基-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-cyclobutyl-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-环丁基-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-cyclobutyl-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-环丁基-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-Cyclobutyl-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-乙氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-乙氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-乙氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-ethoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-Butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

1-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1H-1,2,3-triazole-4-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噻二唑-2-甲酰胺、5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(叔丁基)-N-(3-甲基-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-甲基-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-甲基-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(3-methyl-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噻二唑-2-甲酰胺、5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-thiadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噻二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-thiadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噻二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-thiadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

1-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,2,4,5-四氢-3H-苯并[d]氮杂-3-羧酸叔丁酯、1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine -3-carboxylic acid tert-butyl ester,

(R)-1-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,2,4,5-四氢-3H-苯并[d]氮杂-3-羧酸叔丁酯、(R)-1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine -3-carboxylic acid tert-butyl ester,

(S)-1-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,2,4,5-四氢-3H-苯并[d]氮杂-3-羧酸叔丁酯、(S)-1-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[d]azepine -3-carboxylic acid tert-butyl ester,

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(3-(2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-(2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(3-((S)-2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-((S)-2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-((S)-2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(3-((S)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(3-((R)-2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-((R)-2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-((R)-2-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(3-((R)-2-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(3-(3-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(3-(3-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-Butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(3-(3-羟丙基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(3-(3-hydroxypropyl)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(3,3-二氟环丁基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(3,3-二氟环丁基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(3,3-二氟环丁基)-N-(2-甲基-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(3,3-difluorocyclobutyl)-N-(2-methyl-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(3,3-二氟环丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(3,3-二氟环丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(3,3-二氟环丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(3,3-difluorocyclobutyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(8-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(8-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(8-羟基-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(R)-5-(叔丁基)-N-(8-羟基-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、(R)-5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

(S)-5-(叔丁基)-N-(8-羟基-2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺、(S)-5-(tert-butyl)-N-(8-hydroxy-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide,

5-(叔丁基)-N-(2-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

5-(叔丁基)-N-(2-(2-((1-甲基-5-(三氟甲基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、5-(tert-butyl)-N-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-5-(三氟甲基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(R)-5-(tert-butyl)-N-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

(S)-5-(叔丁基)-N-(2-(2-((1-甲基-5-(三氟甲基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺、(S)-5-(tert-butyl)-N-(2-(2-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide,

1-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1H-1,2,3-三唑-4-甲酰胺、1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1H-1,2,3-triazole-4-carboxamide,

(R)-1-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1H-1,2,3-三唑-4-甲酰胺、(R)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1H-1,2,3-triazole-4-carboxamide,

(S)-1-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1H-1,2,3-三唑-4-甲酰胺、(S)-1-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1H-1,2,3-triazole-4-carboxamide,

N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、N-(2-(2-Hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

(R)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺以及(R)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide and

(S)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-5-(1-甲基环丙基)-1,3,4-噁二唑-2-甲酰胺、(S)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-5-(1-methylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide,

或其药学上可接受的盐。or a pharmaceutically acceptable salt thereof.

本发明还提供(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物27)的晶形：The present invention also provides (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 27)

如本文所用，术语“结晶”是指具有一个晶体结构的固体形式，其中个别分子具有高度均质的、规则的、闭锁的化学构型。As used herein, the term "crystalline" refers to a solid form having a crystal structure in which the individual molecules have a highly homogeneous, regular, locked chemical configuration.

形式AForm A

在一个实施方案中，本发明提供(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形A。In one embodiment, the present invention provides (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide in crystalline form A.

在一方面，晶形A的特征在于至少三个、至少四个或至少五个在选自以下的2θ角处的粉末X射线衍射(PXRD)峰：5.7°、7.9°、9.7°、18.2°、19.0°和22.4°。在一个实施方案中，晶形A的特征在于在选自以下的2θ角处的粉末X射线衍射峰：5.7°、7.9°、9.7°、18.2°、19.0°和22.4°。在一些实施方案中，上文针对晶形A所述的峰的相对强度为至少5％、至少10％或至少15％。在另一个实施方案中，晶形A的特征在于至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少十个、至少十一个、至少十二个、至少十三个、至少十四个、至少十五个、至少十六个、至少十七个或至少十九个在选自以下的2θ角处的PXRD峰：4.3°、5.7°、7.9°、8.7°、9.7°、11.9°、13.1°、14.8°、15.2°、16.1°、17.0°、17.8°、18.2°、19.0°、20.5°、21.2°、22.4°、22.8°、23.8°和25.6°。In one aspect, Form A is characterized by at least three, at least four, or at least five powder X-ray diffraction (PXRD) peaks at 2θ angles selected from: 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°. In one embodiment, Form A is characterized by powder X-ray diffraction peaks at 2θ angles selected from: 5.7°, 7.9°, 9.7°, 18.2°, 19.0°, and 22.4°. In some embodiments, the relative intensity of the peaks described above for Form A is at least 5%, at least 10%, or at least 15%. In another embodiment, Form A is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, or at least nineteen PXRD peaks at 2θ angles selected from 4.3°, 5.7°, 7.9°, 8.7°, 9.7°, 11.9°, 13.1°, 14.8°, 15.2°, 16.1°, 17.0°, 17.8°, 18.2°, 19.0°, 20.5°, 21.2°, 22.4°, 22.8°, 23.8°, and 25.6°.

如本文所用，术语“相对强度”是指感兴趣峰的峰强度对比最大峰的峰强度的比率。As used herein, the term "relative intensity" refers to the ratio of the peak intensity of a peak of interest to the peak intensity of the largest peak.

在另一方面，晶形A具有实质上与图1中所示的PXRD图相同的PXRD图。In another aspect, Form A has a PXRD pattern substantially the same as the PXRD pattern shown in FIG. 1 .

在一方面，晶形A具有实质上与图2中所示的差示扫描量热法(DSC)曲线相同的DSC曲线。具体而言，晶形A的特征在于在DSC曲线中的175.6℃±2℃起始温度。在一个实施方案中，晶形A的熔融温度为186℃±2℃。In one aspect, Form A has a differential scanning calorimetry (DSC) curve substantially the same as the DSC curve shown in Figure 2. Specifically, Form A is characterized by an onset temperature of 175.6°C ± 2°C in the DSC curve. In one embodiment, Form A has a melting temperature of 186°C ± 2°C.

在一方面，晶形A具有实质上与图2中所示的TGA曲线相同的TGA曲线。具体而言，TGA曲线指示晶形A为水合物。In one aspect, Form A has a TGA curve substantially the same as the TGA curve shown in Figure 2. Specifically, the TGA curve indicates that Form A is a hydrate.

如本文所用，“水合物”是指含有(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺和化学计量或非化学计量的并入晶体结构内的水的结晶固体加合物。本领域中已知确定水的存在量的技术包括例如TGA和卡尔-费雪(Karl Fisher,KF)分析。As used herein, "hydrate" refers to a hydrate containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide and a crystalline solid adduct of stoichiometric or non-stoichiometric amounts of water incorporated into the crystal structure. Techniques known in the art for determining the amount of water present include, for example, TGA and Karl Fisher (KF) analysis.

在另一方面，晶形A具有实质上与图3B中所示的相同的固态13C NMR谱。在一个实施方案中，晶形A的特征在于在固态13C NMR谱中的143.7ppm和/或134.4ppm化学位移。形式A谱表现出较宽信号，而不显示清楚的双重信号。形式A谱也表明可能有两种具有不同几何形状的独立分子。在另一个实施方案中，晶形A的特征在于如表3中所示的固态13C NMR谱的化学位移。In another aspect, Form A has a solid-state 13 C NMR spectrum substantially the same as that shown in FIG. 3B . In one embodiment, Form A is characterized by a 143.7 ppm and/or 134.4 ppm chemical shift in the solid-state 13 C NMR spectrum. The Form A spectrum exhibits a broader signal without showing a clear double signal. The Form A spectrum also indicates that there may be two separate molecules with different geometric shapes. In another embodiment, Form A is characterized by a chemical shift in the solid-state 13 C NMR spectrum as shown in Table 3.

在一些实施方案中，晶形A通过例如上文所述的PXRD、DSC、TGA或13NMR或其任何组合表征。在一个实施方案中，晶形A通过单独PXRD或PXRD与上文所述的DSC、TGA和13NMR中的一者或多者的组合表征。In some embodiments, Form A is characterized by, for example, PXRD, DSC, TGA, or 13 NMR as described above, or any combination thereof. In one embodiment, Form A is characterized by PXRD alone or in combination with one or more of DSC, TGA, and 13 NMR as described above.

在一些实施方案中，晶形A为至少70％、80％、85％、90％、95％、97％、99％、99.5％或99.9％纯。形式A的纯度通过将包含化合物(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的组合物中晶形A的重量除以组合物中化合物的总重量来确定。在一个实施方案中，本发明提供一种组合物，其包含化合物(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺，其中组合物中按重量计至少70％、80％、85％、90％、95％、97％、99％、99.5％或99.9％的化合物为化合物的晶形A。In some embodiments, Form A is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% pure. The purity of Form A is determined by combining a crystalline solid phase comprising the compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide composition is determined by dividing the weight of Form A by the total weight of the compounds in the composition. In one embodiment, the present invention provides a composition comprising the compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% by weight of the compound in the composition is crystalline Form A of the compound.

在一个实施方案中，本发明提供一种用于制备(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形A的方法。此方法包括例如由包含(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺和乙醇(EtOH)的浆料形成晶形A。在一个实施方案中，所述方法包括在室温下将含有(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺和EtOH的浆料搅拌1小时至1周，例如1小时、2小时、3小时、4小时、5小时、10小时、15小时、24小时或48小时。In one embodiment, the present invention provides a method for preparing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine This method includes, for example, preparing a crystalline form A of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine. -5-yl)-1H-1,2,3-triazole-4-carboxamide and ethanol (EtOH) to form Form A. In one embodiment, the method comprises adding a slurry containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine to a slurry containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine at room temperature. A slurry of 5-(5-yl)-1H-1,2,3-triazole-4-carboxamide and EtOH is stirred for 1 hour to 1 week, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 24 hours or 48 hours.

形式GForm G

在一个实施方案中，本发明提供(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形G。In one embodiment, the present invention provides (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide, crystalline form G.

在一方面，晶形G的特征在于至少三个、至少四个或至少五个在选自以下的2θ角处的PXRD峰：3.6°、8.9°、10.9°、12.6°、20.2°和21.8°。在一个实施方案中，晶形G的特征在于在选自以下的2θ角处的PXRD峰：3.6°、8.9°、10.9°、12.6°、20.2°和21.8°。在一些实施方案中，上文针对晶形G所述的峰的相对强度为至少5％、至少10％或至少15％。在另一个实施方案中，晶形G的特征在于至少三个、至少四个、至少五个、至少六个、至少七个、至少八个、至少九个、至少十个、至少十一个、至少十二个或至少十三个在选自以下的2θ角处的PXRD峰：3.6°、8.9°、11.0°、12.6°、14.5°、15.4°、16.3°、18.4°、20.2°、21.8°、23.4°、25.4°、26.8°和34.2°。在另一个实施方案中，晶形A的特征在于在选自以下的2θ角处的PXRD峰：3.6°、8.9°、11.0°、12.6°、14.5°、15.4°、16.3°、18.4°、20.2°、21.8°、23.4°、25.4°、26.8°和34.2°。In one aspect, Form G is characterized by at least three, at least four, or at least five PXRD peaks at 2θ angles selected from: 3.6°, 8.9°, 10.9°, 12.6°, 20.2°, and 21.8°. In one embodiment, Form G is characterized by PXRD peaks at 2θ angles selected from: 3.6°, 8.9°, 10.9°, 12.6°, 20.2°, and 21.8°. In some embodiments, the relative intensity of the peaks described above for Form G is at least 5%, at least 10%, or at least 15%. In another embodiment, Form G is characterized by at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, or at least thirteen PXRD peaks at 2θ angles selected from the group consisting of 3.6°, 8.9°, 11.0°, 12.6°, 14.5°, 15.4°, 16.3°, 18.4°, 20.2°, 21.8°, 23.4°, 25.4°, 26.8°, and 34.2°. In another embodiment, Form A is characterized by PXRD peaks at 2θ angles selected from the group consisting of 3.6°, 8.9°, 11.0°, 12.6°, 14.5°, 15.4°, 16.3°, 18.4°, 20.2°, 21.8°, 23.4°, 25.4°, 26.8°, and 34.2°.

在另一方面，晶形G具有实质上与图4中所示的PXRD图相同的PXRD图。In another aspect, Form G has a PXRD pattern substantially the same as the PXRD pattern shown in FIG. 4 .

在一方面，晶形G具有实质上与图5中所示的DSC曲线相同的DSC曲线。具体而言，晶形G的特征在于在DSC曲线中的215.4℃±2℃起始温度。在另一个实施方案中，晶形G的熔融温度为217℃±2℃。In one aspect, Form G has a DSC curve substantially the same as the DSC curve shown in Figure 5. Specifically, Form G is characterized by an onset temperature of 215.4°C ± 2°C in the DSC curve. In another embodiment, Form G has a melting temperature of 217°C ± 2°C.

在一方面，晶形G具有实质上与图5中所示的TGA曲线相同的TGA曲线。具体而言，TGA曲线指示晶形G为无水物。In one aspect, Form G has a TGA curve substantially the same as the TGA curve shown in Figure 5. Specifically, the TGA curve indicates that Form G is an anhydrate.

如本文所用的“无水物”意指晶形在晶格中实质上不包含水，例如，如通过例如TGA分析或其他定量分析所确定，按重量计小于1％。As used herein, "anhydrate" means that the crystalline form contains substantially no water in the crystal lattice, eg, less than 1% by weight as determined by, for example, TGA analysis or other quantitative analysis.

在另一方面，晶形G具有实质上与图6B中所示的相同的固态13C NMR谱。在一个实施方案中，晶形G的特征在于在固态13C NMR谱中的147.0ppm、146.0ppm和/或140.6ppm化学位移。当与表明不对称单元中有两种独立分子的溶液13C NMR谱相比时，形式G的谱显示在芳族区中的峰分裂(双重信号)。在另一个实施方案中，晶形G的特征在于如表3中所示的固态13CNMR谱的化学位移。In another aspect, Form G has a solid state 13 C NMR spectrum substantially the same as that shown in FIG6B. In one embodiment, Form G is characterized by 147.0 ppm, 146.0 ppm and/or 140.6 ppm chemical shifts in the solid state 13 C NMR spectrum. When compared to a solution 13 C NMR spectrum indicating two independent molecules in the asymmetric unit, the spectrum of Form G shows a peak splitting (dual signal) in the aromatic region. In another embodiment, Form G is characterized by the chemical shifts of the solid state 13 C NMR spectrum as shown in Table 3.

在一些实施方案中，晶形G为至少70％、80％、85％、90％、95％、97％、99％、99.5％或99.9％纯。形式G的纯度通过将包含化合物(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的组合物中晶形G的重量除以组合物中化合物的总重量来确定。在一个实施方案中，本发明提供一种组合物，其包含化合物(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺，其中组合物中按重量计至少70％、80％、85％、90％、95％、97％、99％、99.5％或99.9％的化合物为化合物的晶形G。In some embodiments, Form G is at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5%, or 99.9% pure. The purity of Form G is determined by combining a crystalline solid phase comprising the compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide composition is determined by dividing the weight of Form G by the total weight of the compounds in the composition. In one embodiment, the present invention provides a composition comprising the compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide, wherein at least 70%, 80%, 85%, 90%, 95%, 97%, 99%, 99.5% or 99.9% by weight of the compound in the composition is Form G of the compound.

在一个实施方案中，本发明提供一种用于制备(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的晶形G的方法。此方法包括例如由包含(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺和乙酸异丙酯(IPAc)的浆料形成晶形G。在一个实施方案中，所述方法包括在高温(例如，30℃与70℃之间、40℃与60℃之间、45℃与55℃之间或50℃)下将含有(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺和乙酸异丙酯(IPAc)的浆料搅拌1小时至1周，例如1小时、2小时、3小时、4小时、5小时、10小时、15小时、24小时或48小时。In one embodiment, the present invention provides a method for preparing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine This method includes, for example, preparing a crystalline form G of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine. -5-yl)-1H-1,2,3-triazole-4-carboxamide and isopropyl acetate (IPAc) to form Form G. In one embodiment, the method comprises mixing a mixture containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine at an elevated temperature (e.g., between 30°C and 70°C, between 40°C and 60°C, between 45°C and 55°C, or 50°C). A slurry of 1-5-yl)-1H-1,2,3-triazole-4-carboxamide and isopropyl acetate (IPAc) is stirred for 1 hour to 1 week, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 10 hours, 15 hours, 24 hours or 48 hours.

或者，晶形G可通过包括以下步骤的方法制备：(i)通过蒸馏从含有(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺和二氯甲烷的混合物移除至少一部分二氯甲烷；(ii)将乙酸异丙酯(IPAc)添加至混合物；(iii)将含有IPAc的混合物加热至高温(例如，50℃与70℃之间、55℃与65℃之间或60℃)，接着冷却至接近室温(例如，20℃)以形成含有所述化合物和IPAc的浆料；以及(iv)将晶形G从浆料分离。在一个实施方案中，可重复步骤(i)和(ii)一次或多次(例如二、三、四或五次)。在一个实施方案中，重复步骤(i)和(ii)，直至移除实质上所有(例如，按体积计至少60％、至少70％、至少80％、至少90％或至少95％)的二氯甲烷。在一个实施方案中，可重复步骤(iii)中的加热和冷却一次或多次(例如，二、三、四、五、十、十五、二十次或更多次)。Alternatively, Form G may be prepared by a process comprising the steps of: (i) preparing a crystalline form G from a crystalline form containing (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine by distillation -5-yl)-1H-1,2,3-triazole-4-carboxamide and dichloromethane, removing at least a portion of the dichloromethane; (ii) adding isopropyl acetate (IPAc) to the mixture; (iii) heating the mixture containing IPAc to an elevated temperature (e.g., between 50°C and 70°C, between 55°C and 65°C, or 60°C), followed by cooling to near room temperature (e.g., 20°C) to form a slurry containing the compound and IPAc; and (iv) isolating Form G from the slurry. In one embodiment, steps (i) and (ii) may be repeated one or more times (e.g., two, three, four, or five times). In one embodiment, steps (i) and (ii) are repeated until substantially all (e.g., at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by volume) of the dichloromethane is removed. In one embodiment, the heating and cooling in step (iii) may be repeated one or more times (eg, two, three, four, five, ten, fifteen, twenty times or more).

应理解，晶形A或晶形G的PXRD图的2θ值可在仪器之间有所不同，并且可取决于样品制备中的变化。因此，晶形A或晶形G的PXRD峰位置不应理解为绝对值，并且可在±0.2°下变化。It should be understood that the 2θ values of the PXRD patterns of Form A or Form G may vary between instruments and may depend on variations in sample preparation. Therefore, the PXRD peak positions of Form A or Form G should not be understood as absolute values and may vary within ±0.2°.

如本文所意欲，“实质上与图1中所示的相同的PXRD图”、“实质上与图4中所示的相同的PXRD图”、“实质上与图3B中所示的相同”或“实质上与图6B中所示的相同”意指出于比较目的，存在至少80％、至少90％或至少95％的图1、图4、图3B和图6B中所示的峰。应进一步理解，出于比较目的，允许峰位置相对于图1和图4中所示的那些的一些变化性，诸如±0.2°。类似地，出于比较目的，允许峰位置相对于图3B和图6B中所示的那些的一些变化性，诸如±0.5ppm。As intended herein, "substantially the same PXRD pattern as shown in FIG. 1 ," "substantially the same PXRD pattern as shown in FIG. 4 ," "substantially the same as shown in FIG. 3B ," or "substantially the same as shown in FIG. 6B ," means that for comparison purposes, at least 80%, at least 90%, or at least 95% of the peaks shown in FIG. 1 , FIG. 4 , FIG. 3B , and FIG. 6B are present. It should be further understood that for comparison purposes, some variability in peak position relative to those shown in FIG. 1 and FIG. 4 , such as ±0.2°, is allowed. Similarly, for comparison purposes, some variability in peak position relative to those shown in FIG. 3B and FIG. 6B , such as ±0.5 ppm, is allowed.

如本文所用，术语“烷基”是指完全饱和的分支或未分支烃部分。优选的是，烷基包含1至6个碳原子或1至4个碳原子。在一些实施方案中，烷基包含6至20个碳原子。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、第二丁基、异丁基、叔丁基、正戊基、异戊基、新戊基或正己基。As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Preferably, the alkyl group contains 1 to 6 carbon atoms or 1 to 4 carbon atoms. In some embodiments, the alkyl group contains 6 to 20 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

“烯基”是指可为直链或分支链且具有至少一个碳-碳双键的不饱和烃基。具有2-6个碳原子的烯基可为优选的。烯基可含有1、2或3个碳-碳双键或更多碳-碳双键。烯基的实例包括乙烯基、正丙烯基、异丙烯基、正丁-2-烯基、正己-3-烯基及其类似基团。"Alkenyl" refers to an unsaturated hydrocarbon group that may be straight or branched and has at least one carbon-carbon double bond. Alkenyl groups having 2-6 carbon atoms may be preferred. Alkenyl groups may contain 1, 2, or 3 carbon-carbon double bonds or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

“炔基”是指可为直链或分支链且具有至少一个碳-碳参键的不饱和烃基。具有2-6个碳原子的炔基可为优选的。炔基可含有1、2或3个碳-碳参键或更多碳-碳参键。炔基的实例包括乙炔基、正丙炔基、正丁-2-炔基、正己-3-炔基和其类似基团。"Alkynyl" refers to an unsaturated hydrocarbon group which may be straight or branched and has at least one carbon-carbon triple bond. Alkynyl groups having 2-6 carbon atoms may be preferred. Alkynyl groups may contain 1, 2, or 3 carbon-carbon triple bonds or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

基团中的碳原子数在本文中通过前缀“Cx-xx”指定，其中x和xx为整数。例如，“C1-4烷基”为具有1至4个碳原子的烷基。The number of carbon atoms in a group is designated herein by the prefix "C x-xx ", where x and xx are integers. For example, "C 1-4 alkyl" is an alkyl group having 1 to 4 carbon atoms.

“卤素”或“卤基”可为氟、氯、溴或碘。"Halogen" or "halo" may be fluorine, chlorine, bromine or iodine.

如本文所用，术语“杂环基”是指以下饱和或不饱和单环或双环环系(例如，稠环系统、桥联环系统或螺环系统)，其具有3至10个环成员或具体而言3至8个环成员、3至7个环成员、3至6个环成员或5至7个环成员或4至7个环成员，其中至少一者为杂原子，并且其中多至4(例如，1、2、3或4)者可为杂原子，其中所述杂原子独立地选自O、S和N，并且其中C可为氧化的(例如，C(O))，N可为氧化的(例如，N(O))或季铵化的，并且S可任选地被氧化成亚砜和砜。不饱和杂环包括杂芳基环。如本文所用，术语“杂芳基”是指芳族5或6元单环系统，其具有1至4个独立地选自O、S和N的杂原子，并且其中N可为氧化的(例如，N(O))或季铵化的，并且S可任选地被氧化成亚砜和砜。在一个实施方案中，杂环基为3至7元饱和单环或3至6元饱和单环或5至7元饱和单环或4至6元饱和单环。在一个实施方案中，杂环基为3至7元单环或3至6元单环或4至6元单环或5至7元单环。在另一个实施方案中，杂环基为6或7元双环。在又另一个实施方案中，杂环基为4至7元单环非芳环。在另一个实施方案中，杂环基为6至8元螺或桥联双环。杂环基可连接在杂原子或碳原子处。杂环基的实例包括但不限于氮杂环丙烷基、环氧乙烷基、环硫乙烷基、氧杂氮杂环丙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、四氢呋喃基、硫杂环戊烷基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧环戊烷基、二硫环戊烷基、氧硫环戊烷基、哌啶基、四氢吡喃基、硫杂环己烷基、哌嗪基、吗啉基、硫代吗啉基、二噁烷基、二硫杂环己烷基、三噁烷基、三硫杂环己烷基、氮杂环庚烷基、氧杂环庚烷基(oxepanyl)、硫杂环庚烷基(thiepanyl)、二氢呋喃基、咪唑啉基、二氢吡喃基和杂芳基环，包括氮杂环丁二烯基(azetyl)、硫杂环丁二烯基(thietyl)、吡咯基、呋喃基、噻吩基(thiophenyl或thienyl)、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋呫基(furazanyl)、噁二唑基、噻二唑基、二噻唑基、三唑基、四唑基、吡啶基、吡喃基、硫代吡喃基、哌嗪基、嘧啶基、哒嗪基、噁嗪基、噻嗪基、二噁嗪基、二硫杂环己烯基(dithiinyl)、氧杂硫杂环己烷基、三嗪基、四嗪基、氮杂基、氧杂环庚三烯基、硫杂环庚三烯基、二氮杂基和硫氮杂基及其类似基团。As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic ring system (e.g., a fused ring system, a bridged ring system, or a spiro ring system) having 3 to 10 ring members, or specifically 3 to 8 ring members, 3 to 7 ring members, 3 to 6 ring members, or 5 to 7 ring members, or 4 to 7 ring members, at least one of which is a heteroatom, and up to 4 (e.g., 1, 2, 3, or 4) of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S, and N, and wherein C may be oxidized (e.g., C(O)), N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to sulfoxides and sulfones. Unsaturated heterocyclic rings include heteroaryl rings. As used herein, the term "heteroaryl" refers to an aromatic 5 or 6-membered monocyclic ring system having 1 to 4 heteroatoms independently selected from O, S and N, and wherein N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to sulfoxide and sulfone. In one embodiment, the heterocyclic group is a 3 to 7-membered saturated monocyclic ring or a 3 to 6-membered saturated monocyclic ring or a 5 to 7-membered saturated monocyclic ring or a 4 to 6-membered saturated monocyclic ring. In one embodiment, the heterocyclic group is a 3 to 7-membered monocyclic ring or a 3 to 6-membered monocyclic ring or a 4 to 6-membered monocyclic ring or a 5 to 7-membered monocyclic ring. In another embodiment, the heterocyclic group is a 6 or 7-membered bicyclic ring. In yet another embodiment, the heterocyclic group is a 4 to 7-membered monocyclic non-aromatic ring. In another embodiment, the heterocyclic group is a 6 to 8-membered spiro or bridged bicyclic ring. The heterocyclic group may be attached at a heteroatom or a carbon atom. Examples of heterocyclic groups include, but are not limited to, aziridine, oxirane, thioethanethiol, oxaziridine, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl , dihydrofuranyl, imidazolinyl, dihydropyranyl and heteroaryl rings including azetyl, thietyl, pyrrolyl, furanyl, thiophenyl or thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridyl, pyranyl, thiopyranyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxazinyl, dithiinyl, oxathiazinyl, triazinyl, tetrazinyl, azepine Oxepinyl, thiol, diazepine Thiazepine Groups and similar groups.

如本文所用的术语“稠环系统”为具有两个各自独立地选自碳环基或杂环基的环的环系统，其中两个环结构共享两个相邻环原子。稠环系统可具有9至12个环成员。The term "fused ring system" as used herein is a ring system having two rings each independently selected from carbocyclyl or heterocyclyl, wherein the two ring structures share two adjacent ring atoms. The fused ring system may have 9 to 12 ring members.

如本文所用的术语“桥联环系统”为具有碳环基或杂环基环的环系统，其中环的两个非相邻原子通过一个或多个(优选一至三个)选自C、N、O或S的原子连接(桥联)。桥联环系统可具有6至8个环成员。The term "bridged ring system" as used herein is a ring system having a carbocyclyl or heterocyclyl ring in which two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably one to three) atoms selected from C, N, O or S. A bridged ring system may have 6 to 8 ring members.

如本文所用的术语“螺环系统”为具有两个各自独立地选自碳环基或杂环基的环的环系统，其中两个环结构共有一个环原子。螺环系统具有5至8个环成员。The term "spiro ring system" as used herein is a ring system having two rings each independently selected from carbocyclyl or heterocyclyl, wherein the two ring structures have one ring atom in common. The spiro ring system has 5 to 8 ring members.

在一个实施方案中，杂环基为4至6元单环杂环基。4至6元单环杂环系统的实例包括但不限于氮杂环丁烷基、吡咯烷基、四氢呋喃基、硫杂环戊烷基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧环戊烷基、二硫环戊烷基、氧硫环戊烷基、哌啶基、四氢吡喃基、硫杂环己烷基、哌嗪基、吗啉基、硫吗啉基、二噁烷基、二硫杂环己烷基、二氢呋喃基、咪唑啉基、二氢吡喃基、吡咯基、呋喃基、噻吩基(thiophenyl或thienyl)、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋呫基、噁二唑基、噻二唑基、二噻唑基、三唑基、四唑基、吡啶基、吡喃基、噻吡喃基、哌嗪基、嘧啶基、哒嗪基、噁嗪基、噻嗪基、二噁嗪基、二硫杂环己烯基、氧杂硫杂环己烷基、三嗪基和四嗪基。In one embodiment, the heterocyclyl group is a 4- to 6-membered monocyclic heterocyclyl group. Examples of 4- to 6-membered monocyclic heterocyclic ring systems include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithiolanyl, dihydrofuranyl, imidazolinyl, dithiolanyl, dioxanyl, dithiolanyl, dihydrofuranyl, imidazolinyl, dioxanyl, dithiolanyl, dihydrofuranyl, dioxanyl, dithiolanyl, dihydrofuranyl, dioxanyl, dithiolanyl, dioxanyl, dithiolanyl, dihydrofuranyl, dioxan ... 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl, 1-Hydrogenyl,

在另一个实施方案中，杂环基为饱和4至6元单环杂环基。饱和4至6元单环杂环系统的实例包括但不限于氮杂环丁烷基、吡咯烷基、四氢呋喃基、硫杂环戊烷基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧环戊烷基、二硫环戊烷基、氧硫环戊烷基、哌啶基、四氢吡喃基、硫杂环己烷基、哌嗪基、吗啉基、硫吗啉基、二噁烷基和二硫杂环己烯基。在一个实施方案中，饱和4至6元单环杂环基为氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、四氢呋喃基、硫杂环戊烷基、咪唑烷基、吡唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、二氧环戊烷基、二硫环戊烷基、氧硫环戊烷基、哌啶基、四氢吡喃基、硫杂环己烷基、哌嗪基、吗啉基、硫吗啉基或二噁嗪基。在另一个实施方案中，饱和4至6元单环杂环基为氧杂环丁烷基、四氢呋喃基或四氢吡喃基。In another embodiment, the heterocyclyl is a saturated 4 to 6 membered monocyclic heterocyclyl. Examples of saturated 4 to 6 membered monocyclic heterocyclic systems include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thiolanyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithiolanyl. In one embodiment, the saturated 4 to 6-membered monocyclic heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thiacyclohexanyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxazinyl. In another embodiment, the saturated 4 to 6-membered monocyclic heterocyclyl is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl.

如本文所用，术语“碳环基”是指具有3-7个碳原子、3-5、3-6、4-6或5-7个碳原子的饱和或不饱和单环或双环烃基。术语“碳环基”涵盖环烷基和芳基。术语“环烷基“是指具有3-7个碳原子、3-6个碳原子或5-7个碳原子的完全饱和单环或双环或螺烃基。示例性单环碳环基包括但不限于、环丙基、环丁基、环戊基、环己基、环庚基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环丁二烯基、环戊二烯基、环己二烯基、环庚二烯基、苯基和环庚三烯基。示例性双环碳环基包括双环[2.1.1]己基、双环[2.2.1]庚基、双环[2.2.1]庚烯基、三环[2.2.1.02,6]庚基、6,6-二甲基双环[3.1.1]庚基或2,6,6-三甲基双环[3.1.1]庚基、螺[2.2]戊基和螺[3.3]庚基。在一个实施方案中，碳环基为4至6元单环碳环基。在另一个实施方案中，碳环基为3至5元碳环基。在一个实施方案中，碳环基为C4-6≠环烷基。在又一个实施方案中，碳环基为环丁基、环戊基或环己基。As used herein, the term "carbocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon radical having 3-7 carbon atoms, 3-5, 3-6, 4-6 or 5-7 carbon atoms. The term "carbocyclyl" encompasses cycloalkyl and aryl. The term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic or spiro hydrocarbon radical having 3-7 carbon atoms, 3-6 carbon atoms or 5-7 carbon atoms. Exemplary monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl and cycloheptatrienyl. Exemplary bicyclic carbocyclyls include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0 2,6 ]heptyl, 6,6-dimethylbicyclo[3.1.1]heptyl or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentyl and spiro[3.3]heptyl. In one embodiment, the carbocyclyl is a 4 to 6-membered monocyclic carbocyclyl. In another embodiment, the carbocyclyl is a 3 to 5-membered carbocyclyl. In one embodiment, the carbocyclyl is a C 4-6≠ cycloalkyl. In yet another embodiment, the carbocyclyl is a cyclobutyl, cyclopentyl or cyclohexyl.

在本文提供的化合物可呈足以形成稳定无毒酸或碱盐的碱性或酸性的情况下，以药学上可接受的盐形式制备和施用化合物可为适当的。药学上可接受的盐的实例为用形成生理学上可接受的阴离子的酸形成的有机酸加成盐，例如甲苯磺酸盐、甲磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐或α-甘油磷酸盐。还可形成无机盐，包括盐酸盐、硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。In the case where the compounds provided herein may be alkaline or acidic enough to form stable non-toxic acid or base salts, it may be appropriate to prepare and administer the compounds in the form of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as toluenesulfonates, mesylates, acetates, citrates, malonates, tartrates, succinates, benzoates, ascorbates, α-ketoglutarate or α-glycerophosphate. Inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

药学上可接受的盐可使用本领域中熟知的标准程序获得，例如通过使诸如胺的充足碱性化合物与提供生理学上可接受的阴离子的合适酸反应。还可制备羧酸的碱金属(例如钠、钾或锂)或碱土金属(例如钙)盐。Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid providing a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

药学上可接受的碱加成盐可由无机和有机碱制备。由无机碱获得的盐可包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐或镁盐。由有机碱获得的盐可包括但不限于以下各项的盐：伯胺、仲胺或叔胺，诸如烷基胺、二烷基胺、三烷基胺、取代的烷基胺、二(取代的烷基)胺、三(取代的烷基)胺、烯基胺、二烯基胺、三烯基胺、取代的烯基胺、二(取代的烯基)胺、三(取代的烯基)胺、环烷基胺、二(环烷基)胺、三(环烷基)胺、取代的环烷基胺、双取代的环烷基胺、三取代的环烷基胺、环烯基胺、二(环烯基)胺、三(环烯基)胺、取代的环烯基胺、双取代的环烯基胺、三取代的环烯基胺、芳基胺、二芳基胺、三芳基胺、杂芳基胺、二杂芳基胺、三杂芳基胺、杂环胺、二杂环胺、三杂环胺或混合二胺和三胺，其中胺上的至少两个取代基可不同并且可为烷基、取代的烷基、烯基、取代的烯基、环烷基、取代的环烷基、环烯基、取代的环烯基、芳基、杂芳基或杂环基团及其类似基团。还包括其中两个或三个取代基连同氨基氮一起形成杂环烷基或杂芳基的胺。胺的非限制性实例可包括异丙胺、三甲胺、二乙胺、三(异丙基)胺、三(正丙基)胺、乙醇胺、2-二甲基氨基乙醇、缓血酸胺(trimethamine)、赖氨酸、精氨酸、组氨酸、咖啡碱(caffeine)、普鲁卡因(procaine)、海巴明(hydrabamine)、胆碱(choline)、甜菜碱(betaine)、乙二胺、葡糖胺(glucosamine)、N-烷基还原葡糖胺、可可豆碱(theobromine)、嘌呤、哌嗪、哌啶、吗啉或N-乙基哌啶及其类似物。其他羧酸衍生物可适用，例如羧酸酰胺，包括甲酰胺、低级烷基甲酰胺或二烷基甲酰胺及其类似物。Pharmaceutically acceptable alkali addition salts can be prepared from inorganic and organic bases. The salt obtained from inorganic bases may include, but is not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts or magnesium salts. The salt obtained from organic bases may include, but is not limited to, the salts of the following: primary amines, secondary amines or tertiary amines, such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dienylamines, trialnylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(substituted The invention also includes amines comprising amines of the type 1 to 5 amines, wherein the amines are substituted alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heteroaryl, heterocyclic, diheterocyclic, triheterocyclic, or mixed diamines and triamines, wherein at least two substituents on the amine may be different and may be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic groups and the like. Also included are amines wherein the two or three substituents together with the amino nitrogen form a heterocycloalkyl or heteroaryl group. The non-limiting examples of amines can include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkyl reduced glucosamine, theobromine, purine, piperazine, piperidine, morpholine or N-ethylpiperidine and the like. Other carboxylic acid derivatives can be applicable, such as carboxylic acid amides, including formamide, lower alkyl formamide or dialkyl formamide and the like.

如本文所述的化合物或其药学上可接受的盐可在所述分子中含有一个或多个不对称中心。根据本公开内容，不指定立体化学的任何结构均应理解为包括所有呈纯或实质上纯形式的各种立体异构物(例如，非对映异构物和对映异构物)以及其混合物(诸如外消旋混合物或对映异构富集混合物)。本领域中熟知如何制备此类光学活性形式(例如通过再结晶技术解析外消旋形式、通过手性合成由光学活性起始物质合成或使用手性固定相进行色谱分离)。Compounds as described herein or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure that does not specify stereochemistry is understood to include all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). It is well known in the art how to prepare such optically active forms (e.g., by resolving racemic forms by recrystallization techniques, synthesizing from optically active starting materials by chiral synthesis, or by chromatographic separation using chiral stationary phases).

当通过名称或结构描绘化合物的具体立体异构物时，化合物的立体化学纯度为至少20％、30％、40％、50％、60％、70％、80％、90％、95％、97％、99％、99.5％或99.9％。“立体化学纯度“意指所需立体异构物相对于所有立体异构物的合并重量的重量百分比。When a specific stereoisomer of a compound is depicted by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percent of the desired stereoisomer relative to the combined weight of all stereoisomers.

当通过名称或结构描绘化合物的具体对映异构物时，化合物的立体化学纯度为至少20％、30％、40％、50％、60％、70％、80％、90％、95％、97％、99％、99.5％或99.9％。“立化学纯度”意指所需对映异构物相对于所有立体异构物的合并重量的重量百分比。When a specific enantiomer of a compound is depicted by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percent of the desired enantiomer relative to the combined weight of all stereoisomers.

当通过结构来命名或描绘所公开化合物的立体化学，并且命名或描绘的结构涵盖多于一种立体异构物(例如，如以非对映异构物对的形式)时，应理解包括了所涵盖立体异构物之一或所涵盖立体异构物的任何混合物。应进一步理解，命名或描绘的立体异构物的立体异构纯度为至少20％、30％、40％、50％、60％、70％、80％、90％、95％、97％、99％、99.5％或99.9％。立体异构纯度意指通过名称或结构所涵盖的所需立体异构物相对于所有立体异构物的合并重量的重量百分比。When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the form of a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereoisomer purity means the weight percentage of the desired stereoisomer encompassed by the name or structure relative to the combined weight of all stereoisomers.

当通过结构命名或描绘所公开化合物而不指示立体化学，并且所述化合物具有一个手性中心时，应理解所述名称或结构涵盖一种呈纯或实质上纯形式的化合物对映异构物以及其混合物(诸如化合物的外消旋混合物和以一种对映异构物的形式相对于其对应光学异构物富集的混合物)。When a disclosed compound is named or depicted by structure without indication of stereochemistry, and the compound has one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form as well as mixtures thereof (such as racemic mixtures of the compounds and mixtures enriched in one enantiomer relative to its corresponding optical isomer).

当通过结构命名或描绘所公开化合物而不指示立体化学，并且例如所述化合物具有至少两个手性中心时，应理解所述名称或结构涵盖一种呈纯或实质上纯形式的立体异构物以及其混合物(诸如立体异构物的混合物和其中一种或多种立体异构物相对于其他立体异构物富集的立体异构物的混合物)。When a disclosed compound is named or depicted by structure without indicating stereochemistry, and, for example, the compound has at least two chiral centers, it is understood that the name or structure encompasses one stereoisomer in pure or substantially pure form as well as mixtures thereof (such as mixtures of stereoisomers and mixtures of stereoisomers in which one or more stereoisomers are enriched relative to other stereoisomers).

所公开化合物可以互变异构形式存在并且涵盖混合物和单独的个别互变异构物。此外，一些化合物可表达出同质多晶形性。The disclosed compounds may exist in tautomeric forms and encompass mixtures and separate individual tautomers. In addition, some compounds may exhibit polymorphism.

在一个实施方案中，本发明的化合物或其药学上可接受的盐包括氘。In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof include deuterium.

另一个实施方案为一种药物组合物，其包含至少一种本文所述的化合物或其药学上可接受的盐和至少一种药学上可接受的载剂。Another embodiment is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

本文所述的化合物或其药学上可接受的盐可用于减小Btk的活性，或以其他方式影响Btk的性质和/或行为，例如稳定性、磷酸化、激酶活性、与其他蛋白的相互作用等。The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to reduce the activity of Btk, or otherwise affect the properties and/or behavior of Btk, such as stability, phosphorylation, kinase activity, interaction with other proteins, etc.

在一些实施方案中，本发明提供减小Btk酶活性的方法。在一些实施方案中，此类方法包括将Btk与有效量Btk抑制剂接触。因此，本发明进一步提供抑制Btk酶活性的方法，其通过将Btk与本发明的Btk抑制剂接触来进行。In some embodiments, the present invention provides methods for reducing Btk enzyme activity. In some embodiments, such methods include contacting Btk with an effective amount of a Btk inhibitor. Therefore, the present invention further provides a method for inhibiting Btk enzyme activity, which is carried out by contacting Btk with a Btk inhibitor of the present invention.

本发明的一个实施方案包括一种治疗受试者的对Btk的抑制有反应的病症的方法，其包括向所述受试者施用有效量至少一种本文所述的化合物或其药学上可接受的盐。One embodiment of the invention includes a method of treating a condition responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

在一个实施方案中，本发明提供治疗有需要的受试者的自身免疫性病症、炎性病症和癌症的方法，其包括向所述受试者施用有效量至少一种本文所述的化合物或其药学上可接受的盐。In one embodiment, the present invention provides a method of treating autoimmune disorders, inflammatory disorders, and cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

术语“自身免疫性病症”包括涉及针对天然抗原有异常免疫反应的疾病或病症，诸如急性弥漫性脑脊髓炎(ADEM)、爱迪生氏病(Addison's disease)、斑秃、抗磷脂抗体综合征(APS)、自身免疫性溶血性贫血、自身免疫性肝炎、大疱性类天疱疮(BP)、乳糜泻(Coeliacdisease)、皮肌炎、1型糖尿病、古德帕斯彻氏综合症(Goodpasture's syndrome)、格雷氏病(Graves'disease)、格林-巴利综合征(Guillain-Barre syndrome，GBS)、桥本氏病(Hashimoto's disease)、特发性血小板减少性紫癫、红斑狼疮、混合性结缔组织疾病、多发性硬化症、重症肌无力、寻常性天疱疮、恶性贫血、多发性肌炎、原发性胆汁性肝硬化、肖格伦氏综合征(Sjogren's syndrome)、颞动脉炎(temporal arteritis)和韦格纳氏肉芽肿病(Wegener's granulomatosis)。术语“炎性病症”包括涉及急性或慢性炎症的疾病或病症，诸如过敏、气喘、前列腺炎、肾丝球肾炎、盆腔炎(PID)、炎性肠病(IBD，例如克罗恩氏病(Crohn's disease)、溃疡性结肠炎)、再灌注损伤、类风湿性关节炎、移植排斥和血管炎。在一些实施方案中，本发明提供一种治疗类风湿性关节炎或狼疮的方法。在一些实施方案中，本发明提供一种治疗多发性硬化症的方法。The term "autoimmune disorder" includes diseases or disorders involving an abnormal immune response to a natural antigen, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, The term "inflammatory disorder" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. In some embodiments, the present invention provides a method of treating rheumatoid arthritis or lupus. In some embodiments, the present invention provides a method of treating multiple sclerosis.

术语“癌症”包括涉及异常细胞生长和/或增殖的疾病或病症，诸如神经胶质瘤、甲状腺癌、乳腺癌、肺癌(例如小细胞肺癌、非小细胞肺癌)、胃癌、胃肠道基质瘤、胰脏癌、胆管癌、卵巢癌、子宫内膜癌、前列腺癌、肾细胞癌、淋巴瘤(例如，间变性大细胞淋巴瘤)、白血病(例如急性髓样白血病、T细胞白血病、慢性淋巴细胞性白血病)、多发性骨髓瘤、恶性间皮瘤、恶性黑色素瘤和结肠癌(例如微卫星不稳定性-高结肠直肠癌)。在一些实施方案中，本发明提供一种治疗白血病或淋巴瘤的方法。The term "cancer" includes diseases or conditions involving abnormal cell growth and/or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumors, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colorectal cancer). In some embodiments, the present invention provides a method of treating a leukemia or lymphoma.

如本文所用，术语“受试者”和“患者”可互换使用，并且意指需要治疗的哺乳动物，例如伴侣动物(例如，狗、猫及其类似动物)、家畜(例如，母牛、猪、马、绵羊、山羊及其类似动物)和实验动物(例如，大鼠、小鼠、天竺鼠及其类似动物)。通常，受试者为需要治疗的人类。As used herein, the terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, and the like), livestock (e.g., cows, pigs, horses, sheep, goats, and the like), and experimental animals (e.g., rats, mice, guinea pigs, and the like). Typically, the subject is a human in need of treatment.

如本文所用，术语“治疗(treating或treatment)”是指获得所需药理和/或生理效应。效应可为治疗性，其包括部分或实质上达成以下结果中的一者或多者：部分或完全减小疾病、病症或综合征的程度；改善或改进与病症相关的临床症状或指示物；或延迟、抑制或减小疾病、病症或综合征的进展的可能性。As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic, which includes partially or substantially achieving one or more of the following results: partially or completely reducing the extent of a disease, disorder, or syndrome; ameliorating or improving clinical symptoms or indicators associated with the disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

向受试者施用的本文所提供的化合物或其药学上可接受的盐的有效剂量可为10μg-500mg。An effective dose of a compound provided herein or a pharmaceutically acceptable salt thereof administered to a subject may be 10 μg-500 mg.

向哺乳动物施用本文所述的化合物或其药学上可接受的盐包括任何合适的递送方法。向哺乳动物施用本文所述的化合物或其药学上可接受的盐包括向所述哺乳动物局部地、肠内、肠胃外、经皮、经黏膜、经由吸入、脑池内、硬膜外、阴道内、静脉内、肌肉内、皮下、真皮内或玻璃体内施用本文所述的化合物或其药学上可接受的盐。向哺乳动物施用本文所述的化合物或其药学上可接受的盐还包括向哺乳动物局部、肠内、肠胃外、经皮、经黏膜、经由吸入、脑池内、硬膜外、阴道内、静脉内、肌肉内、皮下、真皮内或玻璃体内施用一种化合物，所述化合物在哺乳动物身体内或表面上代谢成本文所述的化合物或其药学上可接受的盐。Administration of a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal includes any suitable delivery method. Administration of a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal includes administration of a compound as described herein or a pharmaceutically acceptable salt thereof to the mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternal, epidural, intravaginal, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administration of a compound as described herein or a pharmaceutically acceptable salt thereof to a mammal also includes administration of a compound topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternal, epidural, intravaginal, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally to a mammal that is metabolized to a compound as described herein or a pharmaceutically acceptable salt thereof in or on the body of the mammal.

因此，如本文所述的化合物或其药学上可接受的盐可与药学上可接受的媒剂(诸如惰性稀释剂或可吸收食用载剂)组合来全身性(例如经口)施用。其可封闭在硬质或软质外壳明胶胶囊中，可压制成片剂，或可直接与患者膳食的食物合并。对于经口治疗性施用，如本文所述的化合物或其药学上可接受的盐可与一种或多种赋形剂组合并且以可摄取片剂、经颊片剂、锭剂、胶囊、酏剂、悬浮液、糖浆或粉片及其类似物形式使用。此类组合物和制剂应含有至少约0.1％的活性化合物。组合物和制剂的百分比当然可改变并且可宜在既定单位剂型的重量的约2％至约60％之间。活性化合物在此类治疗适用组合物中的量可为将获得有效剂量水平的量。Therefore, the compound as described herein or its pharmaceutically acceptable salt can be combined with a pharmaceutically acceptable vehicle (such as an inert diluent or an absorbable edible carrier) for systemic (e.g., oral) administration. It can be enclosed in a hard or soft shell gelatin capsule, can be compressed into tablets, or can be directly combined with the food of the patient's diet. For oral therapeutic administration, the compound as described herein or its pharmaceutically acceptable salt can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups or powder tablets and the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the composition and preparation can certainly be varied and can be preferably between about 2% and about 60% of the weight of a given unit dosage form. The amount of the active compound in such a therapeutically applicable composition can be an amount that will obtain an effective dosage level.

片剂、锭剂、丸剂、胶囊及其类似物可包括以下各项：粘合剂，诸如黄蓍树胶、阿拉伯胶、玉米淀粉或明胶；赋形剂，诸如磷酸二钙；崩解剂，诸如玉米淀粉、马铃薯淀粉、海藻酸及其类似物；润滑剂，诸如硬脂酸镁；或甜味剂，诸如蔗糖、果糖、乳糖或阿斯巴甜(aspartame)或调味剂。Tablets, troches, pills, capsules and the like may include the following: a binder such as gum tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; or a sweetener such as sucrose, fructose, lactose or aspartame or a flavoring agent.

活性化合物也可通过输注或注射静脉内或腹膜内施用。可于水中制备活性化合物或其盐的溶液，任选地与无毒表面活性剂混合。The active compound may also be administered intravenously or intraperitoneally by infusion or injection.Solutions of the active compound or its salts may be prepared in water, optionally mixed with a nontoxic surfactant.

用于注射或输注的示例性药物剂型可包括无菌水溶液或分散液或包含适于临时制备无菌可注射或可输注溶液或分散液的活性成分的无菌散剂。在所有情况下，最终剂型在制造和储存条件下应为无菌、流动和稳定的。Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

可通过在必要时将活性化合物以所需量与如以上列举的各种其他成分一起并入适当溶剂中，随后进行过滤灭菌来制备无菌可注射溶液。在用于制备无菌可注射溶液的无菌粉末的情况下，优选制备方法可为真空干燥和冷冻干燥技术，其可产生活性成分外加存在于先前无菌过滤溶液中的任何其他所需成分的粉末。Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent along with various other ingredients as enumerated above, as necessary, followed by filtered sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation may be vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any other desired ingredients present in the previously sterile-filtered solution.

示例性固体载体可包括精细分散固体，诸如滑石、粘土、微晶纤维素、二氧化硅、氧化铝及其类似物。适用的液体载剂包括如本文所述的化合物或其药学上可接受的盐可任选地藉助于无毒表面活性剂以有效含量溶解或分散于其中的水、醇或二醇或水-醇/二醇共混物。Exemplary solid carriers may include finely divided solids such as talc, clay, microcrystalline cellulose, silicon dioxide, alumina and the like. Suitable liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends in which the compounds described herein or pharmaceutically acceptable salts thereof may be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.

如本文所述的化合物或其药学上可接受的盐的适用剂量可通过在动物模型中比较其体外活性和体内活性来确定。用于将小鼠和其他动物中的有效剂量外推至人类的方法为本领域所知；例如参见美国专利第4,938,949号，其以全文引用的方式并入本文中。The applicable dosage of a compound as described herein or a pharmaceutically acceptable salt thereof can be determined by comparing its in vitro activity and in vivo activity in an animal model. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, for example, U.S. Pat. No. 4,938,949, which is incorporated herein by reference in its entirety.

如本文所述的化合物或其药学上可接受的盐的用于在治疗中使用所需要的量可不仅随所选特定盐而变化，而且也随施用途径、所治疗病状的性质以及患者的年龄和状况而变化并且可最终由主治医师或临床医师裁量。然而，一般而言，剂量可在每天每公斤体重约0.1至约10mg的范围内。The amount of a compound as described herein or a pharmaceutically acceptable salt thereof for use in therapy may vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient and may ultimately be at the discretion of the attending physician or clinician. However, in general, dosages may be in the range of about 0.1 to about 10 mg per kilogram of body weight per day.

如本文所述的化合物或其药学上可接受的盐可宜以单位剂型施用；例如每单位剂型含有0.01至10mg或0.05至1mg活性成分。在一些实施方案中，5mg/kg或更小的剂量可为合适的。The compounds as described herein or their pharmaceutically acceptable salts may be conveniently administered in unit dosage form; for example, each unit dosage form contains 0.01 to 10 mg or 0.05 to 1 mg of active ingredient. In some embodiments, a dose of 5 mg/kg or less may be appropriate.

所需剂量可便利地以单一剂量的形式或呈以适当间隔施用的分剂量呈现。The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

所公开的方法可包括一种试剂盒，其包括如本文所述的化合物或其药学上可接受的盐以及说明性材料，所述材料可描述向细胞或受试者施用如本文所述的化合物或其药学上可接受的盐或包含如本文所述的化合物或其药学上可接受的盐的组合物。这应理解为包括本领域技术人员已知的试剂盒的其他实施方案，诸如包含用于在向细胞或受试者施用如本文所述的化合物或其药学上可接受的盐或组合物之前溶解或悬浮如本文所述的化合物或其药学上可接受的盐或组合物的(诸如无菌)溶剂的试剂盒。在一些实施方案中，受试者可为人类。The disclosed method may include a kit comprising a compound as described herein or a pharmaceutically acceptable salt thereof and illustrative materials that may describe administering a compound as described herein or a pharmaceutically acceptable salt thereof or a composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof to a cell or subject. This should be understood to include other embodiments of kits known to those skilled in the art, such as kits comprising a (such as sterile) solvent for dissolving or suspending a compound as described herein or a pharmaceutically acceptable salt thereof or a composition prior to administering a compound as described herein or a pharmaceutically acceptable salt thereof or a composition to a cell or subject. In some embodiments, the subject may be human.

范例example

LCMS方法：在Waters Acquity UPLC BEH C18 1.7uM 2.1×50mm(零件号186002350机器)上分析样品，MS模式：MS:ESI+扫描范围100-1000道耳顿。PDA检测210-400nm。所利用的方法为于0.1％三氟乙酸(0.1％v/v)中在0.7ml/min下95％水/5％MeCN(初始条件)线性梯度在1min内变至5％H2O/95％MeCN，保持5％H2O/95％MeCN至1.3min，并且注射体积为0.5uL。LCMS Method: Samples were analyzed on a Waters Acquity UPLC BEH C18 1.7uM 2.1×50mm (Part No. 186002350 machine), MS mode: MS:ESI+ scan range 100-1000 Daltons. PDA detection 210-400nm. The method utilized was a linear gradient of 95% water/5% MeCN (initial conditions) in 0.1% trifluoroacetic acid (0.1% v/v) at 0.7 ml/min to 5% H 2 O/95% MeCN in 1 min, holding 5% H 2 O/95% MeCN to 1.3 min, and an injection volume of 0.5uL.

SFC分离：在如以下实施例中所指定的条件的情况下运行每次分离，包括柱名称/零件名称、分离方法、在SFC系统上设定的背压调节器、流率、检测波长、注射体积、样品浓度和样品稀释液。SFC separations: Each separation was run with the conditions as specified in the examples below, including column name/part name, separation method, back pressure regulator set on the SFC system, flow rate, detection wavelength, injection volume, sample concentration, and sample dilution.

实施例1：5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺Example 1: 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,2,4-oxadiazole-3-carboxamide

1.N-(3-溴苯乙基)-4-甲基苯磺酰胺的合成1. Synthesis of N-(3-bromophenethyl)-4-methylbenzenesulfonamide

在0℃下向2-(3-溴苯基)乙胺(2g,10mmol)于CH2Cl2(10mL)中的混合物中添加三乙胺(2.02g,20mmol)和TsCl(2.18g,11.5mmol)。在室温下将混合物搅拌2h，用NaOH(1N,100mL)稀释，并且用CH2Cl2(100mL)萃取。将有机层用水(100mL)、盐水(100mL)洗涤，干燥(Na2SO4)，并且在真空中浓缩，以得到呈黄色油状物的N-(3-溴苯乙基)-4-甲基苯磺酰胺(3.5g，产率：100％)。ESI-MS(M+H)+:354.0。1H NMR(400MHz,CDCl3)δ:7.69(d,J＝8.0Hz,2H),7.34(d,J＝8.4Hz,1H),7.30(d,J＝8.0Hz,2H),7.17(t,J＝1.6Hz,1H),7.13(t,J＝8.0Hz,1H),7.03-7.02(m,1H),4.52(t,J＝6.0Hz,1H),3.22-3.17(m,2H),2.73(t,J＝6.8Hz,2H),2.45(s,3H)。To a mixture of 2-(3-bromophenyl)ethylamine (2 g, 10 mmol) in CH 2 Cl 2 (10 mL) was added triethylamine (2.02 g, 20 mmol) and TsCl (2.18 g, 11.5 mmol) at 0° C. The mixture was stirred at room temperature for 2 h, diluted with NaOH (1 N, 100 mL), and extracted with CH 2 Cl 2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (Na 2 SO 4 ), and concentrated in vacuo to give N-(3-bromophenethyl)-4-methylbenzenesulfonamide (3.5 g, yield: 100%) as a yellow oil. ESI-MS (M+H) + : 354.0. 1 H NMR (400MHz, CDCl 3 ) δ: 7.69 (d, J = 8.0Hz, 2H), 7.34 (d, J = 8.4Hz, 1H), 7.30 (d, J = 8.0Hz, 2H), 7.17 (t, J = 1.6Hz, 1H), 7.13 (t, J = 8.0Hz, 1H), 7.03-7.02 (m, 1 H), 4.52 (t, J = 6.0Hz, 1H), 3.22-3.17 (m, 2H), 2.73 (t, J = 6.8Hz, 2H), 2.45 (s, 3H).

2. 2-(N-(3-溴苯乙基)-4-甲基苯基磺酰氨基)乙酸乙酯的合成2. Synthesis of ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonylamino)acetate

向N-(3-溴苯乙基)-4-甲基苯磺酰胺(7.2g,20mmol)于(CH3)2CO(80mL)中的混合物中添加K2CO3(19.3g,140mmol)和2-溴乙酸乙酯(3.67g,22mmol)。将混合物在60℃下搅拌12h，冷却至室温，并且过滤出盐。将所得滤液在真空中浓缩以得到呈黄色油状物的2-(N-(3-溴苯乙基)-4-甲基苯基磺酰氨基)乙酸乙酯(8.78g，产率：100％)。ESI-MS(M+H)+:440.0。1H NMR(400MHz,CDCl3)δ:7.70(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,1H),7.28(d,J＝8.0Hz,2H),7.14(t,J＝7.6Hz,1H),7.10-7.08(m,2H),4.08(q,J＝7.6Hz,2H),3.98(s,2H),3.44(t,J＝7.6Hz,2H),2.85(t,J＝7.2Hz,2H),2.42(s,3H),1.19(t,J＝7.2Hz,3H)。To a mixture of N-(3-bromophenethyl)-4-methylbenzenesulfonamide (7.2 g, 20 mmol) in (CH 3 ) 2 CO (80 mL) was added K 2 CO 3 (19.3 g, 140 mmol) and ethyl 2-bromoacetate (3.67 g, 22 mmol). The mixture was stirred at 60° C. for 12 h, cooled to room temperature, and the salts were filtered off. The resulting filtrate was concentrated in vacuo to give ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonamido)acetate (8.78 g, yield: 100%) as a yellow oil. ESI-MS (M+H) + : 440.0. 1 H NMR (400MHz, CDCl 3 ) δ: 7.70 (d, J = 8.4Hz, 2H), 7.34 (d, J = 8.4Hz, 1H), 7.28 (d, J = 8.0Hz, 2H), 7.14 (t, J = 7.6Hz, 1H), 7.10-7.08 (m, 2H), 4.08 (q, J = 7.6Hz, 2 H), 3.98 (s, 2H), 3.44 (t, J = 7.6Hz, 2H), 2.85 (t, J = 7.2Hz, 2H), 2.42 (s, 3H), 1.19 (t, J = 7.2Hz, 3H).

3. 2-(N-(3-溴苯乙基)-4-甲基苯基磺酰氨基)乙酸的合成3. Synthesis of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonylamino)acetic acid

向2-(N-(3-溴苯乙基)-4-甲基苯基磺酰氨基)乙酸乙酯(8.78mg,20mmol)于EtOH(40mL)和H2O(40mL)中的溶液中添加NaOH(1.6g,40mmol)。在室温下将反应混合物搅拌12h。然后减少溶剂，并且用HCl(1N)将残余物调整至pH＝3。用EtOAc(100mL×3)萃取混合物。将有机层干燥(Na2SO4)并在真空中浓缩以得到呈黄色固体的2-(N-(3-溴苯乙基)-4-甲基苯基磺酰氨基)乙酸(8.2g，产率：100％)。ESI-MS(M+H)+:412.0。1H NMR(400MHz,CDCl3)δ:7.69(d,J＝8.0Hz,2H),7.34(d,J＝7.6Hz,1H),7.29(d,J＝8.4Hz,2H),7.22(s,1H),7.14(t,J＝8.0Hz,1H),7.08-7.06(m,1H),4.00(s,2H),3.45(t,J＝7.6Hz,2H),2.83(t,J＝7.6Hz,2H),2.42(s,3H)。To a solution of ethyl 2-(N-(3-bromophenethyl)-4-methylphenylsulfonylamino)acetic acid (8.78 mg, 20 mmol) in EtOH (40 mL) and H 2 O (40 mL) was added NaOH (1.6 g, 40 mmol). The reaction mixture was stirred at room temperature for 12 h. The solvent was then reduced and the residue was adjusted to pH=3 with HCl (1 N). The mixture was extracted with EtOAc (100 mL×3). The organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo to give 2-(N-(3-bromophenethyl)-4-methylphenylsulfonylamino)acetic acid (8.2 g, yield: 100%) as a yellow solid. ESI-MS (M+H) + : 412.0. 1 H NMR (400MHz, CDCl 3 ) δ: 7.69 (d, J = 8.0Hz, 2H), 7.34 (d, J = 7.6Hz, 1H), 7.29 (d, J = 8.4Hz, 2H), 7.22 (s, 1H), 7.14 (t, J = 8.0Hz, 1H), 7.08-7.06 (m, 1H), 4.00 (s, 2H), 3.45 (t, J = 7.6Hz, 2H), 2.83 (t, J = 7.6Hz, 2H), 2.42 (s, 3H).

4. 7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂1-酮的合成4. 7-Bromo-3-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine Synthesis of 1-Keto

向2-(N-(3-溴苯乙基)-4-甲基苯基磺酰氨基)乙酸(8.2g,20mmol)于CH2Cl2(100mL)中的溶液中添加SOCl2(11.9g,100mmol)和DMF(催化剂)。将反应混合物在40℃下搅拌1h。然后将溶剂在减压下移除并在真空中干燥2h。将残余物溶解于CH2Cl2(100mL)中并于冰浴中冷却。添加AlCl3(10.56g,80mmol)，并且在0℃至室温下将混合物搅拌12h。将混合物倾倒至浓HCl(20mL)中并用EtOAc(100mL×2)萃取。将有机层用水(100mL)、盐水(100mL)洗涤，干燥(Na2SO4)，并且在真空中浓缩，以得到残余物，将所述残余物通过硅胶柱(石油醚:EtOAc＝4:1)纯化，以得到呈黄色固体的7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂-1-酮(1.88g，产率：24％)。ESI-MS(M+H)+:394.1。1H NMR(400MHz,CDCl3)δ:7.42(d,J＝8.4Hz,2H),7.38(dd,J＝8.4,1.6Hz,1H),7.31-7.29(m,2H),7.14(d,J＝8.0Hz,2H),4.21(s,2H),3.68(t,J＝6.8Hz,2H),2.93(t,J＝7.2Hz,2H),2.39(s,3H)。To a solution of 2-(N-(3-bromophenethyl)-4-methylphenylsulfonylamino)acetic acid (8.2 g, 20 mmol) in CH 2 Cl 2 (100 mL) was added SOCl 2 (11.9 g, 100 mmol) and DMF (catalyst). The reaction mixture was stirred at 40° C. for 1 h. The solvent was then removed under reduced pressure and dried in vacuo for 2 h. The residue was dissolved in CH 2 Cl 2 (100 mL) and cooled in an ice bath. AlCl 3 (10.56 g, 80 mmol) was added, and the mixture was stirred at 0° C. to room temperature for 12 h. The mixture was poured into concentrated HCl (20 mL) and extracted with EtOAc (100 mL×2). The organic layer was washed with water (100 mL), brine (100 mL), dried (Na 2 SO 4 ), and concentrated in vacuo to give a residue that was purified by silica gel column (petroleum ether: EtOAc = 4: 1) to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid. -1-one (1.88g, yield: 24%). ESI-MS(M+H) + :394.1. 1 H NMR (400MHz, CDCl 3 ) δ: 7.42 (d, J = 8.4Hz, 2H), 7.38 (dd, J = 8.4, 1.6Hz, 1H), 7.31-7.29 (m, 2H), 7.14 (d, J = 8.0Hz, 2H), 4.21 (s, 2H), 3.68 (t, J = 6.8Hz, 2H), 2.93(t,J=7.2Hz,2H),2.39(s,3H).

5. 7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂1-胺的合成5. 7-Bromo-3-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine Synthesis of 1-amine

7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂-1-胺的合成类似于实施例2的合成。将残余物通过硅胶柱(CH2Cl2:MeOH＝20:1)纯化，以得到呈黄色固体的7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂-1-胺(154mg，产率：64％)。ESI-MS(M+H)+:395.1。1H NMR(400MHz,CDCl3)δ:7.66(d,J＝8.4Hz,2H),7.37(d,J＝8.4Hz,2H),7.31(dd,J＝8.4,1.6Hz,1H),7.27(d,J＝1.6Hz,1H),7.18(d,J＝8.4Hz,1H),4.12-4.40(m,1H),3.42-3.36(m,2H),3.19-3.12(m,2H),2.96-2.89(m,2H),2.41(s,3H)。7-Bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine The synthesis of -1-amine was similar to that of Example 2. The residue was purified by silica gel column (CH 2 Cl 2 :MeOH=20:1) to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid. -1-amine (154 mg, yield: 64%). ESI-MS(M+H) + :395.1. 1 H NMR (400MHz, CDCl 3 ) δ: 7.66 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.4Hz, 2H), 7.31 (dd, J = 8.4, 1.6Hz, 1H), 7.27 (d, J = 1.6Hz, 1H), 7.18 (d, J = 8.4Hz, 1H), 4.12-4.40 (m,1H),3.42-3.36(m,2H),3.19-3.12(m,2H),2.96-2.89(m,2H),2.41(s,3H).

6. 7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂1-胺的合成6. 7-Bromo-3-toluenesulfonyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine Synthesis of 1-amine

在70℃下将7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂-1-胺(1.2g,3.04mmol)于HBr/HOAc(33％,20mL)中的混合物搅拌12h。冷却之后，将混合物用EtOAc(60mL)稀释，并且将所得沉淀物过滤并在真空下干燥，以得到呈白色固体的7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂-1-胺(870mg，产率：71％)。ESI-MS(M+H)+:241.1。1H NMR(400MHz,CDCl3)δ:7.65-7.63(m,2H),7.25(d,J＝8.8Hz,1H),5.17-5.14(m,1H),3.84-3.80(m,1H),3.69-3.65(m,1H),3.44-3.40(m,2H),3.27-3.14(m,2H)。7-Bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine was heated at 70 °C. A mixture of -1-amine (1.2 g, 3.04 mmol) in HBr/HOAc (33%, 20 mL) was stirred for 12 h. After cooling, the mixture was diluted with EtOAc (60 mL), and the resulting precipitate was filtered and dried under vacuum to give 7-bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a white solid. -1-amine (870 mg, yield: 71%). ESI-MS (M+H) + : 241.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.65-7.63 (m, 2H), 7.25 (d, J=8.8 Hz, 1H), 5.17-5.14 (m, 1H), 3.84-3.80 (m, 1H), 3.69-3.65 (m, 1H), 3.44-3.40 (m, 2H), 3.27-3.14 (m, 2H).

7. 1-氨基-7-溴-4,5-二氢-1H-苯并[d]氮杂3(2H)-羧酸叔丁酯的合成7. 1-Amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine Synthesis of tert-butyl 3(2H)-carboxylate

向7-溴-3-甲苯磺酰基-2,3,4,5-四氢-1H-苯并[d]氮杂-1-胺(680mg,1.7mmol)和三乙胺(515mg,5.1mmol)于CH2Cl2(10mL)中的混合物中添加Boc2O(333mg,1.0mmol)。在室温下将混合物搅拌2h。用CH2Cl2(100mL)稀释之后，将有机层用水(30mL)和盐水(30mL)洗涤，干燥(Na2SO4)，过滤，并且在真空中浓缩，以得到呈黄色油状物的1-氨基-7-溴-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯(450mg，产率：77％)。ESI-MS(M+H)+:341.0。1H NMR(400MHz,CDCl3)δ:7.31(d,J＝8.0Hz,1H),7.26(s,1H),7.19-7.11(m,1H),4.17-4.10(m,1H),3.83-3.66(m,2H),3.48-3.45(m,1H),3.37-3.14(m,2H),2.78-2.73(m,1H),1.47(s,9H)。7-Bromo-3-tosyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine To a mixture of 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine (680 mg, 1.7 mmol) and triethylamine (515 mg, 5.1 mmol) in CH 2 Cl 2 (10 mL) was added Boc 2 O (333 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 h. After dilution with CH 2 Cl 2 (100 mL), the organic layer was washed with water (30 mL) and brine (30 mL), dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine as a yellow oil. -3(2H)-carboxylic acid tert-butyl ester (450 mg, yield: 77%). ESI-MS (M+H) + : 341.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.31 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.19-7.11 (m, 1H), 4.17-4.10 (m, 1H), 3.83-3.66 (m, 2H), 3.48-3.45 (m, 1H), 3.37-3.14 (m, 2H), 2.78-2.73 (m, 1H), 1.47 (s, 9H).

8. 7-溴-1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[d]氮杂3(2H)-羧酸叔丁酯的合成8. 7-Bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine Synthesis of tert-butyl 3(2H)-carboxylate

在0℃下向5-(叔丁基)-1,2,4-噁二唑-3-羧酸钾(358mg,1.5mmol)于CH2Cl2(10mL)中的混合物中添加(COCl)2(567mg,4.5mmol)和DMF(催化剂)。在室温下将混合物搅拌1h。将混合物浓缩。将残余物在真空中干燥，然后溶解于CH2Cl2(10mL)中，添加1-氨基-7-溴-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯(408mg,1.5mmol)和三乙胺(454mg,4.5mmol)。在室温下将混合物搅拌12h，并且用CH2Cl2(100mL)稀释。将有机相用水(50mL)和盐水(50mL)洗涤并浓缩。将残余物通过硅胶柱(PE(石油醚):EtOAc(乙酸乙酯)＝4:1)纯化，以得到呈白色固体的7-溴-1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯(290mg，产率：38％)。ESI-MS(M+H-56)+:437.0。1H NMR(400MHz,CD3OD)δ:7.42-7.38(m,2H),7.26(d,J＝7.6Hz,1H),5.39(d,J＝5.2Hz,1H),4.14-4.08(m,1H),4.01-3.87(m,1H),3.75-3.70(m,2H),3.56-3.46(m,1H),3.24-3.15(m,1H),3.00-2.91(m,1H),1.48(s,9H),1.38(s,9H)。To a mixture of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (358 mg, 1.5 mmol) in CH 2 Cl 2 (10 mL) at 0° C. was added (COCl) 2 (567 mg, 4.5 mmol) and DMF (catalyst). The mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was dried in vacuo and then dissolved in CH 2 Cl 2 (10 mL), 1-amino-7-bromo-4,5-dihydro-1H-benzo[d]azepine was added. -3 (2H) -carboxylic acid tert-butyl ester (408mg, 1.5mmol) and triethylamine (454mg, 4.5mmol). The mixture was stirred at room temperature for 12h and diluted with CH2Cl2 (100mL). The organic phase was washed with water (50mL) and brine (50mL) and concentrated. The residue was purified by silica gel column (PE (petroleum ether): EtOAc (ethyl acetate) = 4: 1) to obtain 7-bromo-1- (5- (tert-butyl) -1,2,4- oxadiazole -3- formamido) -4,5- dihydro -1H- benzo [d] azepine as a white solid. -3(2H)-carboxylic acid tert-butyl ester (290 mg, yield: 38%). ESI-MS (M+H-56) + : 437.0. 1 H NMR (400 MHz, CD 3 OD) δ: 7.42-7.38 (m, 2H), 7.26 (d, J=7.6 Hz, 1H), 5.39 (d, J=5.2 Hz, 1H), 4.14-4.08 (m, 1H), 4.01-3.87 (m, 1H), 3.75-3.70 (m, 2H), 3.56-3.46 (m, 1H), 3.24-3.15 (m, 1H), 3.00-2.91 (m, 1H), 1.48 (s, 9H), 1.38 (s, 9H).

9. 2-氯-4-甲氧基嘧啶的合成9. Synthesis of 2-chloro-4-methoxypyrimidine

在0℃下向2,4-二氯嘧啶(7.5g,50mmol)于MeOH(80mL)中的溶液中逐滴添加NaOMe(2.84g,52.5mmol)于MeOH(20mL)中的溶液。在0℃下将反应混合物搅拌2h。在真空中将反应混合物浓缩以得到粗产物。将粗产物倾倒至150mL水中。用EtOAc(100mL)萃取水相。将有机层用Na2SO4干燥并在真空中浓缩以得到呈淡黄色固体的2-氯-4-甲氧基嘧啶(5.9g，产率：82％)。ESI-MS(M+H)+:145.0。1H NMR(400MHz,CDCl3)δ:8.27(d,J＝6.0Hz,1H),6.65(d,J＝6.0Hz,1H),3.99(s,3H)。To a solution of 2,4-dichloropyrimidine (7.5 g, 50 mmol) in MeOH (80 mL) was added dropwise a solution of NaOMe (2.84 g, 52.5 mmol) in MeOH (20 mL) at 0 ° C. The reaction mixture was stirred for 2 h at 0 ° C. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was poured into 150 mL of water. The aqueous phase was extracted with EtOAc (100 mL). The organic layer was dried with Na 2 SO 4 and concentrated in vacuo to give 2-chloro-4-methoxypyrimidine (5.9 g, yield: 82%) as a light yellow solid. ESI-MS (M+H) + : 145.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.27 (d, J=6.0 Hz, 1H), 6.65 (d, J=6.0 Hz, 1H), 3.99 (s, 3H).

10. 4-甲氧基-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成10. Synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

向2-氯-4-甲氧基嘧啶(120g,0.83mol)于二噁烷(2L)的溶液中添加1-甲基-1H-吡唑-4-胺盐酸盐(111g,0.83mol)、Cs2CO3(0.83kg,2.5mol)、S-Phos(13.3g,0.03mol)和Pd2(dba)3(16.7g,0.02mol)。在120℃、N2下将反应混合物搅拌4h。将反应混合物冷却至室温，并且添加水(4L)。分离各层并用EtOAc(3×2L)萃取水相。将合并的有机层用盐水(3L)洗涤，干燥(Na2SO4)，并且浓缩。将粗物质通过硅胶色谱法(PE:EtOAc＝5:1至1:1)纯化，以得到呈棕褐色固体的4-甲氧基-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(73g，产率：43％)。ESI-MS(M+H)+:205.8。To a solution of 2-chloro-4-methoxypyrimidine (120 g, 0.83 mol) in dioxane (2 L) was added 1-methyl-1H-pyrazol-4-amine hydrochloride (111 g, 0.83 mol), Cs 2 CO 3 (0.83 kg, 2.5 mol), S-Phos (13.3 g, 0.03 mol) and Pd 2 (dba) 3 (16.7 g, 0.02 mol). The reaction mixture was stirred at 120 °C under N 2 for 4 h. The reaction mixture was cooled to room temperature and water (4 L) was added. The layers were separated and the aqueous phase was extracted with EtOAc (3×2 L). The combined organic layers were washed with brine (3 L), dried (Na 2 SO 4 ), and concentrated. The crude material was purified by silica gel chromatography (PE:EtOAc=5:1 to 1:1) to give 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (73 g, yield: 43%) as a tan solid. ESI-MS (M+H) + : 205.8.

11. 4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成11. Synthesis of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

向4-甲氧基-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(1.4kg,6.8mol)中添加HBr(11.2L，38％水溶液)。将反应混合物加热至100℃，并且在所述温度下搅拌2h。浓缩反应混合物，然后添加POCl3(11.2L)。将反应混合物加热至100℃，并且在所述温度下搅拌16h。将反应混合物冷却至室温并浓缩。将水(10L)添加至残余物，并且用NaOH水溶液(4M)将溶液的pH调整至pH＝14。用EtOAc(3×10L)萃取碱性水相。将合并的有机层用盐水(9L)洗涤，干燥(Na2SO4)，并且浓缩。将粗物质通过硅胶色谱法(PE:EtOAc＝5:1至2:1)纯化，以得到呈白色固体的4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(770g，产率：54％)。ESI-MS(M+H)+:210.0。To 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.4 kg, 6.8 mol) was added HBr (11.2 L, 38% aqueous solution). The reaction mixture was heated to 100°C and stirred at that temperature for 2 h. The reaction mixture was concentrated and then POCl 3 (11.2 L) was added. The reaction mixture was heated to 100°C and stirred at that temperature for 16 h. The reaction mixture was cooled to room temperature and concentrated. Water (10 L) was added to the residue and the pH of the solution was adjusted to pH=14 with aqueous NaOH solution (4 M). The basic aqueous phase was extracted with EtOAc (3×10 L). The combined organic layers were washed with brine (9 L), dried (Na 2 SO 4 ), and concentrated. The crude material was purified by silica gel chromatography (PE:EtOAc=5:1 to 2:1) to give 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (770 g, yield: 54%) as a white solid. ESI-MS (M+H) + : 210.0.

12. 1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂3(2H)-羧酸叔丁酯的合成12. 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine Synthesis of tert-butyl 3(2H)-carboxylate

在N2下向7-溴-1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯(510mg,1.03mmol)和PinB-BPin(263mg,1.0mmol)于无水1,4-二噁烷(10mL)中的混合物中快速添加KOAc(303mg,3.09mmol)和Pd(dppf)Cl2·CH2Cl2(81mg,0.1mmol)。在100℃、N2下将混合物搅拌12h。冷却之后，添加4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(237mg,1.13mmol)、K2CO3(213mg,1.54mmol)和H2O(2.5mL)。在100℃、N2下将混合物搅拌12h。冷却之后，将混合物浓缩并通过硅胶柱(CH2Cl2:PE:EtOAc＝1:1:1)纯化，以得到呈黄色固体的1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯(250mg，产率：41％)。ESI-MS(M+H)+:588.2。1H NMR(400MHz,CD3OD)δ:8.41(d,J＝4.8Hz,1H),7.99-7.98(m,3H),7.64(s,1H),7.49(d,J＝8.4Hz,1H),7.21(d,J＝5.2Hz,1H),5.54-5.47(m,1H),4.18-4.05(m,1H),3.97-3.90(m,4H),3.87-3.76(m,2H),3.65-3.57(m,1H),3.15-3.11(m,1H),1.49(s,9H),1.39(s,9H)。7-Bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine was added under N2 To a mixture of tert-butyl-3(2H)-carboxylate (510 mg, 1.03 mmol) and PinB-BPin (263 mg, 1.0 mmol) in anhydrous 1,4-dioxane (10 mL) were quickly added KOAc (303 mg, 3.09 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (81 mg, 0.1 mmol). The mixture was stirred at 100° C. under N 2 for 12 h. After cooling, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (237 mg, 1.13 mmol), K 2 CO 3 (213 mg, 1.54 mmol) and H 2 O (2.5 mL) were added. The mixture was stirred at 100° C. under N 2 for 12 h. After cooling, the mixture was concentrated and purified by silica gel column ( CH2Cl2 : PE: EtOAc = 1: 1: 1) to give 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine as a yellow solid. -tert-Butyl 3(2H)-carboxylate (250 mg, yield: 41%). ESI-MS (M+H) + : 588.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.41 (d, J = 4.8Hz, 1H), 7.99-7.98 (m, 3H), 7.64 (s, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.21 (d, J = 5.2Hz, 1H), 5.54-5.47 (m, 1H), 4.18-4 .05(m,1H),3.97-3.90(m,4H),3.87-3.76(m,2H),3.65-3.57(m,1H),3.15-3.11(m,1H),1.49(s,9H),1.39(s,9H).

13. 5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂1-基)-1,2,4-噁二唑-3-甲酰胺的合成13. 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine Synthesis of 1-methyl)-1,2,4-oxadiazole-3-carboxamide

向TFA(1mL)于CH2Cl2(2mL)中的溶液中添加1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯(230mg,0.39mmol)。将混合物在室温下搅拌1h，然后浓缩并通过制备型HPLC(CH3CN/水NH4HCO3 0.05％作为流动相)纯化，以得到5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺(120mg，产率：58％)。ESI-MS(M+H)+:488.3。1H NMR(400MHz,CD3OD)δ:8.37-8.35(m,1H),7.95(s,1H),7.91-7.88(m,2H),7.63(s,1H),7.46(d,J＝7.6Hz,1H),7.15(d,J＝4.8Hz,1H),5.34(d,J＝7.2Hz,1H),3.95(s,3H),3.24-3.19(m,1H),3.11-3.08(m,3H),2.99-2.94(m,2H),1.49(s,9H)。To a solution of TFA (1 mL) in CH2Cl2 (2 mL ) was added 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine -tert-Butyl 3(2H)-carboxylate (230 mg, 0.39 mmol). The mixture was stirred at room temperature for 1 h, then concentrated and purified by preparative HPLC (CH 3 CN/water NH 4 HCO 3 0.05% as mobile phase) to give 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,2,4-oxadiazole-3-carboxamide (120 mg, yield: 58%). ESI-MS (M+H) + : 488.3. 1 H NMR (400 MHz, CD 3 OD) δ: 8.37-8.35 (m, 1H), 7.95 (s, 1H), 7.91-7.88 (m, 2H), 7.63 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.15 (d, J=4.8 Hz, 1H), 5.34 (d, J=7.2 Hz, 1H), 3.95 (s, 3H), 3.24-3.19 (m, 1H), 3.11-3.08 (m, 3H), 2.99-2.94 (m, 2H), 1.49 (s, 9H).

实施例2.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物2)Example 2. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 2)

方法1：Method 1:

1. 3-(3-溴-苄基氨基)-丙酸乙酯1. 3-(3-Bromo-benzylamino)-propionic acid ethyl ester

向3-氨基丙酸乙酯(46.0g,0.3mol)和3-溴苯甲醛(55.5g,0.3mol)于MeOH(1.2L)中的溶液中分批添加三乙胺(60.7g,0.6mol)和NaCNBH3(56.5g,0.9mol)。在室温下将所得混合物搅拌4h。将反应混合物在真空中浓缩，并且将残余物用水(600mL)稀释。用EtOAc(3×500mL)萃取混合物。将合并的有机层用盐水(100mL)洗涤，在无水Na2SO4上干燥，过滤，并且在真空中浓缩，以得到呈淡黄色油状物的3-(3-溴-苄基氨基)-丙酸乙酯(46.5g，产率：54％)。1H NMR(DMSO-d6,300MHz):δ7.52(s,1H),7.40(d,J＝7.5Hz,1H),7.31-7.25(m,2H),4.04(q,J＝7.2Hz,2H),3.67(s,2H),2.69(t,J＝7.2Hz,2H),2.42(t,J＝6.9Hz,2H),1.17(t,J＝6.9Hz,3H)。To a solution of ethyl 3-aminopropionate (46.0 g, 0.3 mol) and 3-bromobenzaldehyde (55.5 g, 0.3 mol) in MeOH (1.2 L) was added triethylamine (60.7 g, 0.6 mol) and NaCNBH 3 (56.5 g, 0.9 mol) in batches. The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with water (600 mL). The mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to obtain ethyl 3- (3-bromo-benzylamino) -propionate (46.5 g, yield: 54%) as a light yellow oil. 1 H NMR (DMSO-d 6 , 300MHz): δ7.52 (s, 1H), 7.40 (d, J = 7.5Hz, 1H), 7.31-7.25 (m, 2H), 4.04 (q, J = 7.2Hz, 2H), 3.67 (s, 2H), 2.69 (t, J = 7.2Hz, 2H), 2.42 (t, J =6.9Hz,2H),1.17(t,J=6.9Hz,3H).

2. 3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酸乙酯的制备2. Preparation of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester

在室温下向3-(3-溴-苄基氨基)-丙酸乙酯(45.6g,0.16mol)于吡啶(500mL)中的溶液中添加TosCl(61.0g,0.32mol)。在120℃下将反应混合物搅拌16h。在真空中移除溶剂以得到粗产物。将粗产物通过硅胶柱色谱法(石油醚:EtOAc＝10:1至5:1)纯化，以得到呈淡黄色油状物的3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酸乙酯(61g，产率：88％)。1HNMR(DMSO-d6,300MHz):δ7.74(d,J＝8.4Hz,2H),7.49-7.41(m,4H),7.31(d,J＝5.1Hz,2H),4.33(s,2H),3.93(q,J＝7.2Hz,2H),3.32(t,J＝7.2Hz,2H),2.41(s,3H),2.36(t,J＝6.9Hz,2H),1.10(t,J＝6.9Hz,3H)。To a solution of 3-(3-bromo-benzylamino)-propionic acid ethyl ester (45.6 g, 0.16 mol) in pyridine (500 mL) was added TosCl (61.0 g, 0.32 mol) at room temperature. The reaction mixture was stirred at 120 ° C for 16 h. The solvent was removed in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc = 10: 1 to 5: 1) to give 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester (61 g, yield: 88%) as a light yellow oil. 2 .41(s,3H),2.36(t,J＝6.9Hz,2H) , 1.10(t,J＝6.9Hz,3H).

3. 3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酸的制备3. Preparation of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid

向3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酸乙酯(60.0g,0.14mol)于EtOH(600mL)和H2O(60mL)的混合溶剂中分批添加NaOH(11.2g,0.28mol)，在60℃下将反应溶液搅拌4h。将反应溶液冷却至0℃并用浓HCl酸化至pH＝5。将溶剂在真空中浓缩以得到残余物，用EtOAc(3×150mL)萃取所述残余物。将有机层用Na2SO4干燥，过滤，并且在真空中浓缩以得到呈白色固体的3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酸(45.2g，产率：78.6％)。1H NMR(DMSO-d6,300MHz):δ12.28(br,1H),7.74(d,J＝8.1Hz,2H),7.49-7.41(m,4H),7.32(d,J＝5.1Hz,2H),4.33(s,2H),3.29(t,J＝6.9Hz,2H),2.41(s,3H),2.27(t,J＝7.5Hz,2H)。To 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid ethyl ester (60.0 g, 0.14 mol) in a mixed solvent of EtOH (600 mL) and H 2 O (60 mL) was added NaOH (11.2 g, 0.28 mol) in portions, and the reaction solution was stirred at 60° C. for 4 h. The reaction solution was cooled to 0° C. and acidified to pH=5 with concentrated HCl. The solvent was concentrated in vacuo to give a residue, which was extracted with EtOAc (3×150 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo to give 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g, yield: 78.6%) as a white solid. 1 H NMR (DMSO-d 6 , 300MHz): δ 12.28 (br, 1H), 7.74 (d, J = 8.1Hz, 2H), 7.49-7.41 (m, 4H), 7.32 (d, J = 5.1Hz, 2H), 4.33 (s, 2H), 3.29 (t, J = 6.9Hz, 2H), 2.41 (s, 3H), 2.27 (t, J = 7.5Hz, 2H).

4. 3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酰氯的制备4. Preparation of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride

向3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酸(45.2g,0.11mol)于CH2Cl2(1000mL)中的溶液中逐滴添加DMF(1mL)并分批添加草酰氯(27.9g,0.22mol)。在55℃下将反应溶液搅拌2h。将混合物在真空中浓缩以得到呈黑色油状物的粗3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酰氯(47.2g，产率：99％)，其用于下一步骤而无需进一步纯化。To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionic acid (45.2 g, 0.11 mol) in CH 2 Cl 2 (1000 mL) was added DMF (1 mL) dropwise and oxalyl chloride (27.9 g, 0.22 mol) was added portionwise. The reaction solution was stirred at 55° C. for 2 h. The mixture was concentrated in vacuo to give crude 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propanoyl chloride (47.2 g, yield: 99%) as a black oil, which was used in the next step without further purification.

5. 8-溴-2-(甲苯-4-磺酰基)-1,2,3,4-四氢-苯并[c]氮杂5-酮的制备5. 8-Bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepine Preparation of 5-ketone

在室温下向3-[(3-溴-苄基)-(甲苯-4-磺酰基)-氨基]-丙酰氯(47.0g,0.11mol)于无水CH2Cl2(1200mL)中的溶液中分批添加AlCl3(29.3g,0.22mol)。在55℃下将反应混合物搅拌2h。将反应混合物倾倒至冰水(1.2L)中并用(500mL)萃取。在真空中将有机层浓缩以得到粗产物。将粗产物通过硅胶柱色谱法(石油醚:EtOAc＝5:1至2:1)纯化，以得到呈白色固体的8-溴-2-(甲苯-4-磺酰基)-1,2,3,4-四氢-苯并[c]氮杂-5-酮(35g，产率：81％)。1H NMR(DMSO-d6,300MHz):δ7.65(d,J＝8.4Hz,3H),7.60-7.51(m,2H),7.36(d,J＝8.1Hz,2H),4.68(s,2H),3.42(t,J＝9.2Hz,2H),2.96(t,J＝6.3Hz,2H),2.37(s,3H)。To a solution of 3-[(3-bromo-benzyl)-(toluene-4-sulfonyl)-amino]-propionyl chloride (47.0 g, 0.11 mol) in anhydrous CH 2 Cl 2 (1200 mL) was added AlCl 3 (29.3 g, 0.22 mol) in portions at room temperature. The reaction mixture was stirred at 55° C. for 2 h. The reaction mixture was poured into ice water (1.2 L) and extracted with (500 mL). The organic layer was concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc = 5: 1 to 2: 1) to give 8-bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepine as a white solid. -5-one (35g, yield: 81%). 1 H NMR (DMSO-d 6 ,300MHz): δ7.65(d,J＝8.4Hz,3H),7.60-7.51(m,2H),7.36(d,J＝8.1Hz,2H),4.68(s,2H),3.42(t,J＝9.2Hz,2H),2.96(t,J＝6.3Hz,2H),2.3 7(s,3H).

6.[8-溴-2-(甲苯-4-磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基]-氨基甲酸叔丁酯的制备6. [8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of tert-butyl 5-amino-1-[(5-yl)-carbamate]

在室温下向8-溴-2-(甲苯-4-磺酰基)-1,2,3,4-四氢-苯并[c]氮杂-5-酮(32.0g,0.08mol)于EtOH(600mL)中的溶液中分批添加NH4OAc(18.5g,0.24mol)和NaCNBH3(14.9g,0.24mol)。然后在95℃下将反应混合物搅拌16h。将混合物倾倒至冰水(500mL)中，然后在真空中移除EtOH。用CH2Cl2(3×500mL)萃取残余物。将合并的溶剂浓缩。在室温下将残余物再溶解于CH2Cl2(300mL)中并添加三乙胺(12.2g,0.12mol)和(Boc)2O(34.6g,0.12mol)。在室温下将混合物搅拌4h，然后在真空中浓缩，以得到粗产物。将粗产物通过硅胶柱色谱法(石油醚:EtOAc＝8:1至2:1)纯化，以得到呈白色固体的[8-溴-2-(甲苯-4-磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基]-氨基甲酸叔丁酯(16.7g，产率：42％)。1HNMR(DMSO d6,300MHz):δ7.62-7.51(m,2H),7.47(d,J＝9.9Hz,1H),7.41-7.34(m,3H),7.10(d,J＝8.4Hz,1H),4.81-4.74(m,1H),4.53(d,J＝15.0Hz,1H),4.28(d,J＝15.3Hz,1H),3.64-3.57(m,1H),3.41-3.30(m,1H),2.35(s,3H),1.85-1.77(m,1H),1.69-1.63(m,1H),1.36(s,9H)。8-Bromo-2-(toluene-4-sulfonyl)-1,2,3,4-tetrahydro-benzo[c]azepine was added at room temperature To a solution of -5-ketone (32.0 g, 0.08 mol) in EtOH (600 mL) were added NH 4 OAc (18.5 g, 0.24 mol) and NaCNBH 3 (14.9 g, 0.24 mol) in portions. The reaction mixture was then stirred at 95 °C for 16 h. The mixture was poured into ice water (500 mL) and the EtOH was then removed in vacuo. The residue was extracted with CH 2 Cl 2 (3×500 mL). The combined solvents were concentrated. The residue was redissolved in CH 2 Cl 2 (300 mL) at room temperature and triethylamine (12.2 g, 0.12 mol) and (Boc) 2 O (34.6 g, 0.12 mol) were added. The mixture was stirred at room temperature for 4 h and then concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: EtOAc = 8: 1 to 2: 1) to give [8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a white solid -5-yl]-carbamic acid tert-butyl ester (16.7 g, yield: 42%). 1 H NMR (DMSO d 6 , 300 MHz): δ 7.62-7.51 (m, 2H), 7.47 (d, J=9.9 Hz, 1H), 7.41-7.34 (m, 3H), 7.10 (d, J=8.4 Hz, 1H), 4.81-4.74 (m, 1H), 4.53 (d, J=15.0 Hz, 1H), 4.28 (d, J=15.3 Hz, 1H), 3.64-3.57 (m, 1H), 3.41-3.30 (m, 1H), 2.35 (s, 3H), 1.85-1.77 (m, 1H), 1.69-1.63 (m, 1H), 1.36 (s, 9H).

7. 8-溴-2-(甲苯-4-磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基胺的制备7. 8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-aminobenzylamine

在25℃下将[8-溴-2-(甲苯-4-磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基]-氨基甲酸叔丁酯(14.8g,0.03mol)于HCl/EtOAc(150mL)中的溶液搅拌4h。将所得固体过滤并用MeOH和Et2O洗涤，以得到呈白色固体的产物8-溴-2-(甲苯-4-磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基胺(10.5g，产率：89％)。1H NMR(DMSO-d6,300MHz):δ8.79(br,3H),7.64-7.58(m,3H),7.53(s,1H),7.36(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,1H),4.71-4.61(m,2H),4.31(d,J＝15.3Hz,1H),3.82(d,J＝18.3Hz,1H),2.38(s,3H),2.14-2.07(m,1H),1.77-1.71(m,1H)。LC-MS:m/z 395.0/397.0[M+H]+。[8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine A solution of tert-butyl]-5-yl-carbamate (14.8 g, 0.03 mol) in HCl/EtOAc (150 mL) was stirred for 4 h. The resulting solid was filtered and washed with MeOH and Et 2 O to give the product 8-bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a white solid. -5-ylamine (10.5g, yield: 89%). 1 H NMR (DMSO-d 6 ,300MHz): δ8.79(br,3H),7.64-7.58(m,3H),7.53(s,1H),7.36(d,J＝8.4Hz,2H),7.15(d,J＝8.4Hz,1H),4.71-4.61(m,2H),4.31(d,J＝1 5.3Hz, 1H), 3.82 (d, J = 18.3Hz, 1H), 2.38 (s, 3H), 2.14-2.07 (m, 1H), 1.77-1.71 (m, 1H). LC-MS: m/z 395.0/397.0[M+H] + .

8. 8-溴-2,3,4,5-四氢-1H-苯并[c]氮杂5-胺的合成8. 8-Bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-amine

在50℃下将8-溴-2-(甲苯-4-磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基胺(2.00g,5.06mmol)于HBr(33％于乙酸中的溶液，20mL)中的溶液加热12h。冷却至室温之后，将混合物用EtOAc(50mL)稀释。将白色固体通过过滤收集并在真空中干燥，以得到粗产物8-溴-2,3,4,5-四氢-1H-苯并[c]氮杂-5-胺(1.66g，产率：82％)，其直接用于下一步骤。ESI-MS(M+H)+241.1。1H NMR(400MHz,CD3OD)δ:7.72-7.55(m,2H),7.18(d,J＝8.4Hz,1H),4.99-4.98(m,1H),4.51(d,J＝14.4Hz,1H),4.39(d,J＝14.4Hz,1H),3.62-3.49(m,2H),2.38-2.24(m,1H),2.16-2.00(m,1H)。8-Bromo-2-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was added at 50°C. A solution of -5-ylamine (2.00 g, 5.06 mmol) in HBr (33% solution in acetic acid, 20 mL) was heated for 12 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL). The white solid was collected by filtration and dried in vacuo to give the crude product 8-bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-amine (1.66 g, yield: 82%), which was used directly in the next step. ESI-MS (M+H) + 241.1. 1 H NMR (400 MHz, CD 3 OD) δ: 7.72-7.55 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 4.99-4.98 (m, 1H), 4.51 (d, J=14.4 Hz, 1H), 4.39 (d, J=14.4 Hz, 1H), 3.62-3.49 (m, 2H), 2.38-2.24 (m, 1H), 2.16-2.00 (m, 1H).

9. 5-氨基-8-溴-4,5-二氢-1H-苯并[c]氮杂2(3H)-羧酸叔丁酯的合成9. 5-Amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine Synthesis of tert-butyl 2(3H)-carboxylate

向8-溴-2,3,4,5-四氢-1H-苯并[c]氮杂-5-胺(640mg,1.60mmol)和三乙胺(490mg,4.8mmol)于CH2Cl2(20mL)中的溶液中添加(Boc)2O(314mg,1.44mmol)。在室温下将混合物搅拌1h。用CH2Cl2(100mL)稀释之后，将混合物用盐水(20mL×2)洗涤。将有机相在真空中浓缩，并且将残余物通过制备型HPLC(具有0.05％NH3.H2O的CH3CN/H2O作为流动相)纯化，以得到呈无色油状物的5-氨基-8-溴-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(364mg，产率：67％)。ESI-MS(M+H)+:341.1。8-Bromo-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of -5-amine (640 mg, 1.60 mmol) and triethylamine (490 mg, 4.8 mmol) in CH 2 Cl 2 (20 mL) was added (Boc) 2 O (314 mg, 1.44 mmol). The mixture was stirred at room temperature for 1 h. After dilution with CH 2 Cl 2 (100 mL), the mixture was washed with brine (20 mL×2). The organic phase was concentrated in vacuo, and the residue was purified by preparative HPLC (CH 3 CN/H 2 O with 0.05% NH 3 .H 2 O as mobile phase) to give 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine as a colorless oil. -2(3H)-carboxylic acid tert-butyl ester (364 mg, yield: 67%). ESI-MS (M+H) + : 341.1.

10. 8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂2(3H)-羧酸叔丁酯的制备10. 8-Bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine Preparation of tert-butyl 2(3H)-carboxylate

8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯的合成类似于实施例1步骤8中7-溴-1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯的合成。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(4.5 g，产率：70％)。ESI-MS(M+H)+:493.3。8-Bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine The synthesis of tert-butyl-2(3H)-carboxylate was similar to that of 7-bromo-1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[d]azepine in step 8 of Example 1. The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine as a yellow solid . -tert-Butyl 2(3H)-carboxylate (4.5 g, yield: 70%). ESI-MS (M+H) + : 493.3.

11. 5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂2(3H)-羧酸叔丁酯的制备11. 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine Preparation of tert-butyl 2(3H)-carboxylate

5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯的合成类似于实施例1步骤12中1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯的制备。将粗产物通过硅胶柱色谱法(EtOAc/MeOH＝15:1)纯化，以得到呈黄色固体的5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(1.2g，产率：28％)。ESI-MS(M+H)+:588.3。1H NMR(400MHz,CD3OD)δ:8.43-8.38(m,1H),8.11-7.95(m,3H),7.67-7.48(m,2H),7.25-7.24(m,1H),5.67-5.63(m,1H),4.84-4.77(m,1H),4.55-4.50(m,1H),4.17-4.09(m,1H),3.94-3.88(m,3H),3.64-3.54(m,1H),2.11-2.08(m,2H),1.43-1.34(m,9H),1.22(s,9H)。5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine The synthesis of tert-butyl-2(3H)-carboxylate was similar to that of 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine in step 12 of Example 1. -3(2H)-carboxylic acid tert-butyl ester. The crude product was purified by silica gel column chromatography (EtOAc/MeOH=15:1) to give 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine as a yellow solid. -tert-Butyl 2(3H)-carboxylate (1.2 g, yield: 28%). ESI-MS (M+H) + : 588.3. 1 H NMR (400MHz, CD 3 OD) δ:8.43-8.38(m,1H),8.11-7.95(m,3H),7.67-7.48(m,2H),7.25-7.24(m,1H),5.67-5.63(m,1H),4.84-4.77(m,1H),4.55-4 .50(m,1H),4.17-4.09(m,1H),3.94-3.88(m,3H),3.64-3.54(m,1H),2.11-2.08(m,2H),1.43-1.34(m,9H),1.22(s,9H).

12. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的制备12. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

向5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(600mg,1.0mmol)于CH2Cl2(5mL)中的溶液中添加TFA(5mL)，在室温下将混合物搅拌1h。浓缩之后，将粗产物(440mg，产率：85％)用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:488.3。To 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine To a solution of tert-butyl-2(3H)-carboxylate (600 mg, 1.0 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 mL), and the mixture was stirred at room temperature for 1 h. After concentration, the crude product (440 mg, yield: 85%) was used in the next step without further purification. ESI-MS (M+H) + : 488.3.

13. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的制备13. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

向5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(180mg,0.36mmol)和二氢呋喃-3(2H)-酮(132mg,1.8mmol)于MeOH(20mL)中的溶液中添加NaBH3CN(66mg,1.08mmol)和ZnCl2(246mg,1.8mmol)。在室温下将混合物搅拌16h。浓缩并用水(30mL)稀释之后，用EtOAc(80mL×2)萃取混合物。将合并的有机层用H2O(60mL)洗涤并浓缩。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(114mg，产率：49％)。ESI-MS(M+H)+:544.3。1H NMR(400MHz,CD3OD)δ:8.30(d,J＝5.2Hz,1H),7.92-7.85(m,3H),7.51(s,1H),7.35(d,J＝8.4Hz,1H),7.11(d,J＝5.2Hz,1H),5.50(d,J＝9.6Hz,1H),4.67-4.55(m,4H),3.84-3.70(m,3H),3.80(s,3H),2.95-2.89(m,1H),2.76-2.72(m,1H),2.15-2.12(m,1H),1.95-1.92(m,1H),1.40(s,9H)。To 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1,2-dihydrofuran-3(2H)-one (132 mg, 1.8 mmol) and 1,5-dihydrofuran-1,2,4-oxadiazole-3-carboxamide (180 mg, 0.36 mmol) in MeOH (20 mL) were added NaBH 3 CN (66 mg, 1.08 mmol) and ZnCl 2 (246 mg, 1.8 mmol). The mixture was stirred at room temperature for 16 h. After concentration and dilution with water (30 mL), the mixture was extracted with EtOAc (80 mL×2). The combined organic layers were washed with H 2 O (60 mL) and concentrated. The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (114 mg, yield: 49%). ESI-MS (M+H) + : 544.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.30 (d, J = 5.2Hz, 1H), 7.92-7.85 (m, 3H), 7.51 (s, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.11 (d, J = 5.2Hz, 1H), 5.50 (d, J = 9.6Hz, 1H), 4.67- 4.55(m,4H),3.84-3.70(m,3H),3.80(s,3H),2.95-2.89(m,1H),2.76-2.72(m,1H),2.15-2.12(m,1H),1.95-1.92(m,1H),1.40(s,9H).

14.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的制备14. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

使5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺经历SFC分离(OD-H(2×25cm)，30％甲醇/CO2，100巴，60mL/min，220nm，注射体积：1.5mL，9mg/mL，甲醇)并产生34.8mg峰1(化学纯度99％，ee>99％)和37.1mg峰2(化学纯度99％，ee>99％)。5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide was subjected to SFC separation (OD-H (2×25 cm), 30% methanol/CO 2 , 100 bar, 60 mL/min, 220 nm, injection volume: 1.5 mL, 9 mg/mL, methanol) and produced 34.8 mg of peak 1 (chemical purity 99%, ee>99%) and 37.1 mg of peak 2 (chemical purity 99%, ee>99%).

峰2被指定为5-叔丁基-1,2,4-噁二唑-3-羧酸{(R)-8-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2-氧杂环丁烷-3-基-2,3,4,5-四氢-1H-2-苯并氮杂-5-基}-酰胺：LCMS:Rt 0.88min，m/z 544.00。1H NMR(400MHz,甲醇-d4)δ8.40(d,J＝5.02Hz,1H),7.87-8.09(m,3H),7.63(s,1H),7.45(d,J＝8.28Hz,1H),7.20(d,J＝5.27Hz,1H),5.60(s,1H),4.55-4.77(m,4H),3.89(s,3H),3.75-3.85(m,3H),2.75-3.10(m,2H),1.89-2.42(m,2H),1.51(s,9H)。Peak 2 was assigned to 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid {(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepine -5-yl}-amide: LCMS: Rt 0.88 min, m/z 544.00. 1H NMR (400 MHz, methanol-d4) δ 8.40 (d, J = 5.02 Hz, 1H), 7.87-8.09 (m, 3H), 7.63 (s, 1H), 7.45 (d, J = 8.28 Hz, 1H), 7.20 (d, J = 5.27 Hz, 1H), 5.60 (s, 1H), 4.55-4.77 (m, 4H), 3.89 (s, 3H), 3.75-3.85 (m, 3H), 2.75-3.10 (m, 2H), 1.89-2.42 (m, 2H), 1.51 (s, 9H).

方法2Method 2

1.手性拆分5-氨基-8-溴-4,5-二氢-1H-苯并[c]氮杂2(3H)-羧酸叔丁酯以得到具有(11bS)-4-羟基二萘并[2,1-d:1',2'-f][1,3,2]二氧杂磷杂环庚三烯4氧化物的(R)-5-氨基-8-溴-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯化合物(1:1)1. Chiral resolution of 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine 2(3H)-carboxylic acid tert-butyl ester to give (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine with (11bS)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphine 4-oxide 2-Carboxylic acid tert-butyl ester compound (1:1)

向5-氨基-8-溴-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(800g,2.34mol)中添加MeOH(4.8L)和(S)-(-)-1,1'-联萘-2,2'-二基磷酸氢酯(816.6g,2.34mol)。将混合物在25℃下搅拌30min并形成黄色浆料。将浆料在回流(70℃)下搅拌以得到黄色溶液。将混合物浓缩至干燥并添加IPAc(3.44L)。将混合物加热至70℃并在所述温度下搅拌3h。将反应混合物冷却至室温，并且添加另一份IPAc(3.44L)。在室温下继续搅拌反应混合物16h。将浆料在离心机上过滤，并且将滤饼洗涤三次，每次用7体积IPAc。将湿滤饼短暂干燥以得到呈白色固体的具有(11bS)-4-羟基二萘并[2,1-d:1',2'-f][1,3,2]二氧杂磷杂环庚三烯4氧化物的(R)-5-氨基-8-溴-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯化合物(1:1)(515g，产率：64％([假定最大回收率为50％]，91.3％ee)。可重复再结晶过程以将ee增加至97.2％。5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine -2 (3H) -carboxylic acid tert-butyl ester (800g, 2.34mol) was added with MeOH (4.8L) and (S) -(-) -1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (816.6g, 2.34mol). The mixture was stirred at 25 ° C for 30min and a yellow slurry was formed. The slurry was stirred at reflux (70 ° C) to obtain a yellow solution. The mixture was concentrated to dryness and IPAc (3.44L) was added. The mixture was heated to 70 ° C and stirred at the temperature for 3h. The reaction mixture was cooled to room temperature and another portion of IPAc (3.44L) was added. The reaction mixture was continued to stir at room temperature for 16h. The slurry was filtered on a centrifuge and the filter cake was washed three times, each time with 7 volumes of IPAc. The wet cake was dried briefly to give (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine with (11bS)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphine 4-oxide as a white solid. -2-carboxylic acid tert-butyl ester compound (1:1) (515 g, yield: 64% ([assuming a maximum recovery of 50%], 91.3% ee). The recrystallization process can be repeated to increase the ee to 97.2%.

2.(R)-8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的制备2. (R)-8-Bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Preparation of tert-butyl 2-carboxylate

向5-(叔丁基)-1,2,4-噁二唑-3-羧酸钾(800mg,4.0mmol)和草酰氯(2.0g,16mmol)于CH2Cl2(10mL)中的溶液中添加DMF(催化剂)。将混合物在室温下搅拌2h，然后用CH2Cl2浓缩两次。将残余物用CH2Cl2(20mL)稀释，并且添加具有(11bR)-4-羟基二萘并[2,1-d:1',2'-f][1,3,2]二氧杂磷杂环庚三烯4氧化物的(R)-5-氨基-8-溴-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯化合物(1:1)(2.0g,3.0mmol)和三乙胺(900mg,9.0mmol)。将混合物在室温下搅拌2h并浓缩。将粗产物通过硅胶色谱法(PE:EtOAc＝2:1)纯化，以得到呈黄色固体的(R)-8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.2g，产率：80％)。ESI-MS(M+Na)+:515.1。1H NMR(400MHz,CDCl3)δ:7.48-7.36(m,2H),7.24-7.18(m,1H),5.61-5.50(m,1H),4.70-4.51(m,1H),4.38-4.29(m,1H),4.05-3.85(m,1H),3.53-3.48(m,1H),2.24-2.16(m,2H),1.48(s,9H),1.40-1.37(m,9H)。To a solution of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (800 mg, 4.0 mmol) and oxalyl chloride (2.0 g, 16 mmol) in CH 2 Cl 2 (10 mL) was added DMF (catalyst). The mixture was stirred at room temperature for 2 h and then concentrated twice with CH 2 Cl 2. The residue was diluted with CH 2 Cl 2 (20 mL) and (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine with (11bR)-4-hydroxydinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphine 4-oxide was added. -2-carboxylic acid tert-butyl ester compound (1: 1) (2.0 g, 3.0 mmol) and triethylamine (900 mg, 9.0 mmol). The mixture was stirred at room temperature for 2 h and concentrated. The crude product was purified by silica gel chromatography (PE: EtOAc = 2: 1) to give (R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (1.2 g, yield: 80%). ESI-MS (M+Na) + : 515.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.48-7.36 (m, 2H), 7.24-7.18 (m, 1H), 5.61-5.50 (m, 1H), 4.70-4.51 (m, 1H), 4.38-4.29 (m, 1H), 4.05-3.85 (m, 1H), 3.53-3.48 (m, 1H), 2.24-2.16 (m, 2H), 1.48 (s, 9H), 1.40-1.37 (m, 9H).

3.(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成3. (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于实施例1步骤12中1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯的合成。将粗物质通过硅胶色谱法(EtOAc:MeOH＝15:1)纯化，以得到呈黄色固体的(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.5g，产率：43％)。ESI-MS(M+H)+:588.3。(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that of 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine in step 12 of Example 1. -3-(2H)-carboxylic acid tert-butyl ester. The crude material was purified by silica gel chromatography (EtOAc:MeOH=15:1) to give (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (1.5 g, yield: 43%). ESI-MS (M+H) + : 588.3.

4.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的合成4. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

向(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.4g,2.3mmol)于CH2Cl2(10mL)中的溶液中添加TFA(10mL)。在室温下将混合物搅拌1h。将反应混合物浓缩并将粗产物(1.0g，产率：81％)用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:488.3。To (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine To a solution of tert-butyl-2-carboxylate (1.4 g, 2.3 mmol) in CH 2 Cl 2 (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the crude product (1.0 g, yield: 81%) was used in the next step without further purification. ESI-MS (M+H) + : 488.3.

5.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺(I-RP33)的合成5. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-amino-1,2,4-oxadiazole-3-carboxamide (I-RP33)

(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于上文在方法1步骤13中所述的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗物质通过硅胶色谱法(EtOAc:MeOH＝20:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(746mg，Y：67％)。ESI-MS(M+H)+:544.3。1H NMR(400MHz,CD3OD)δ:8.42(d,J＝5.2Hz,1H),8.03-7.96(m,3H),7.63(s,1H),7.48(d,J＝8.0Hz,1H),7.23(d,J＝5.2Hz,1H),5.61(d,J＝9.6Hz,1H),4.78-4.67(m,4H),3.96-3.82(m,3H),3.90(s,3H),3.06-3.02(m,1H),2.89-2.80(m,1H),2.29-2.22(m,1H),2.07-2.03(m,1H),1.52(s,9H)。(R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that described above in step 13 of method 1. The crude material was purified by silica gel chromatography (EtOAc:MeOH=20:1) to afford (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (746 mg, Y: 67%). ESI-MS (M+H) + : 544.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.42 (d, J = 5.2Hz, 1H), 8.03-7.96 (m, 3H), 7.63 (s, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.23 (d, J = 5.2Hz, 1H), 5.61 (d, J = 9.6Hz, 1H), 4.78- 4.67(m,4H),3.96-3.82(m,3H),3.90(s,3H),3.06-3.02(m,1H),2.89-2.80(m,1H),2.29-2.22(m,1H),2.07-2.03(m,1H),1.52(s,9H).

实施例3. 5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物3)Example 3. 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 3)

向5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(200mg,0.41mmol)于CH3CN(20mL)中的溶液中添加2-碘乙醇(141mg,0.82mmol)和K2CO3(170mg,1.23mmol)。在80℃下将混合物搅拌2h。将混合物用EtOAc(100mL)稀释，用水(60mL)洗涤，并且浓缩。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(90mg，产率：32％)。ESI-MS(M+H)+:532.3。1HNMR(400MHz,CD3OD)δ:8.43(d,J＝5.2Hz,1H),8.04-8.00(m,3H),7.64(s,1H),7.47(d,J＝8.0Hz,1H),7.25(d,J＝5.0Hz,1H),5.60(d,J＝9.6Hz,1H),4.22-4.10(m,2H),3.91(s,3H),3.75(t,J＝6.0Hz,2H),3.28-3.21(m,2H),2.69-2.65(m,2H),2.31-2.27(m,1H),2.00-1.97(m,1H),1.53(s,9H)。To 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-(( 1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4- yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl- 1H -pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid was added 2-iodoethanol (141 mg, 0.82 mmol) and K 2 CO 3 (170 mg, 1.23 mmol). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with EtOAc (100 mL), washed with water (60 mL), and concentrated. The crude product was purified by preparative HPLC (CH 3 CN/H 2 O with 0.05% NH 4 HCO 3 as mobile phase) to give 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (90 mg, yield: 32%). ESI-MS (M+H) + : 532.3. 1 HNMR (400MHz, CD 3 OD) δ: 8.43 (d, J = 5.2Hz, 1H), 8.04-8.00 (m, 3H), 7.64 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.25 (d, J = 5.0Hz, 1H), 5.60 (d, J = 9.6Hz, 1H), 4.22- 4.10(m,2H),3.91(s,3H),3.75(t,J＝6.0Hz,2H),3.28-3.21(m,2H),2.69-2.65(m,2H),2.31-2.27(m,1H),2.00-1.97(m,1H),1.53(s,9H).

实施例4. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物4)Example 4. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 4)

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例15中5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(98mg，产率：60％)。ESI-MS(M+H)+:566.2。1H NMR(400MHz,CDCl3)δ:8.45(d,J＝4.8Hz,1H),8.02(s,1H),7.94-7.92(m,2H),7.57-7.48(m,3H),7.07(d,J＝5.2Hz,1H),6.96(s,1H),5.72(t,J＝8.8Hz,1H),4.85-4.81(m,1H),4.57-4.53(m,1H),4.03-3.97(m,1H),3.93(s,3H),3.66-3.63(m,1H),2.74(s,3H),2.39-2.21(m,2H),1.49(s,9H)。5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in Example 15 was similar to that of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (98 mg, yield: 60%). ESI-MS (M+H) + : 566.2. 1 H NMR (400MHz, CDCl 3 ) δ: 8.45 (d, J = 4.8Hz, 1H), 8.02 (s, 1H), 7.94-7.92 (m, 2H), 7.57-7.48 (m, 3H), 7.07 (d, J = 5.2Hz, 1H), 6.96 (s, 1H), 5.72 (t, J = 8.8Hz, 1 H),4.85-4.81(m,1H),4.57-4.53(m,1H),4.03-3.97(m,1H),3.93(s,3H),3.66-3.63(m,1H),2.74(s,3H),2.39-2.21(m,2H),1.49(s,9H).

实施例5. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物5)Example 5. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 5)

向5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(180mg,0.36mmol)和二氢呋喃-3(2H)-酮(132mg,1.8mmol)于MeOH(20mL)中的溶液中添加NaBH3CN(66mg,1.08mmol)和ZnCl2(246mg,1.8mmol)。在室温下将混合物搅拌16h。浓缩并用水(30mL)稀释之后，用EtOAc(80mL×2)萃取混合物。将合并的有机层用H2O(60mL)洗涤并浓缩。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(114mg，产率：49％)。ESI-MS(M+H)+:544.3。1H NMR(400MHz,CD3OD)δ:8.30(d,J＝5.2Hz,1H),7.92-7.85(m,3H),7.51(s,1H),7.35(d,J＝8.4Hz,1H),7.11(d,J＝5.2Hz,1H),5.50(d,J＝9.6Hz,1H),4.67-4.55(m,4H),3.84-3.70(m,3H),3.80(s,3H),2.95-2.89(m,1H),2.76-2.72(m,1H),2.15-2.12(m,1H),1.95-1.92(m,1H),1.40(s,9H)。To 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1,2-dihydrofuran-3(2H)-one (132 mg, 1.8 mmol) and 1,5-dihydrofuran-1,2,4-oxadiazole-3-carboxamide (180 mg, 0.36 mmol) in MeOH (20 mL) were added NaBH 3 CN (66 mg, 1.08 mmol) and ZnCl 2 (246 mg, 1.8 mmol). The mixture was stirred at room temperature for 16 h. After concentration and dilution with water (30 mL), the mixture was extracted with EtOAc (80 mL×2). The combined organic layers were washed with H 2 O (60 mL) and concentrated. The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (114 mg, yield: 49%). ESI-MS (M+H) + : 544.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.30 (d, J = 5.2Hz, 1H), 7.92-7.85 (m, 3H), 7.51 (s, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.11 (d, J = 5.2Hz, 1H), 5.50 (d, J = 9.6Hz, 1H), 4.67- 4.55(m,4H),3.84-3.70(m,3H),3.80(s,3H),2.95-2.89(m,1H),2.76-2.72(m,1H),2.15-2.12(m,1H),1.95-1.92(m,1H),1.40(s,9H).

实施例6. 5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物6)Example 6. 5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 6)

5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例5中5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物通过硅胶色谱法(EtOAc:MeOH＝10:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-(2-(3-羟基环丁基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(102mg，产率：53％)。ESI-MS(M+H)+:557.7。1H NMR(400MHz,CD3OD)δ:8.29(d,J＝5.2Hz,1H),7.87(s,3H),7.50(s,1H),7.32(d,J＝8.8Hz,1H),7.09(d,J＝5.6Hz,1H),5.45(d,J＝10.0Hz,1H),3.86-3.78(m,3H),3.75(s,3H),3.09-3.06(m,1H),2.80-2.74(m,1H),2.50-2.39(m,3H),2.14-2.05(m,1H),1.88-1.85(m,1H),1.72-1.69(m,2H),1.41(s,9H)。5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in Example 5 was similar. The crude product was purified by silica gel chromatography (EtOAc:MeOH=10:1) to give 5-(tert-butyl)-N-(2-(3-hydroxycyclobutyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (102 mg, yield: 53%). ESI-MS (M+H) + : 557.7. 1 H NMR (400MHz, CD 3 OD) δ: 8.29 (d, J = 5.2Hz, 1H), 7.87 (s, 3H), 7.50 (s, 1H), 7.32 (d, J = 8.8Hz, 1H), 7.09 (d, J = 5.6Hz, 1H), 5.45 (d, J = 10.0Hz, 1H), 3.86-3.78 (m,3H),3.75(s,3H),3.09-3.06(m,1H),2.80-2.74(m,1H),2.50-2.39(m,3H),2.14-2.05(m,1H),1.88-1.85(m,1H),1.72-1.69(m,2H),1.41(s,9H ).

实施例7. 5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物7)Example 7. 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 7)

1. 4-甲氧基-N-(1-乙基-1H-吡唑-4-基)嘧啶-2-胺的合成1. Synthesis of 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

4-甲氧基-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成类似于实施例1步骤10中4-甲氧基-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成。将粗物质通过硅胶色谱法(PE:EtOAc＝1:1)纯化，以得到呈棕褐色固体的4-甲氧基-N-(1-乙基-1H-吡唑-4-基)嘧啶-2-胺(420mg，产率：43％)。ESI-MS(M+H)+:220.1。The synthesis of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine was similar to that of 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine in step 10 of Example 1. The crude material was purified by silica gel chromatography (PE:EtOAc=1:1) to give 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (420 mg, yield: 43%) as a tan solid. ESI-MS (M+H) + : 220.1.

2. 4-氯-N-(1-乙基-1H-吡唑-4-基)嘧啶-2-胺的合成2. Synthesis of 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine

向4-甲氧基-N-(1-乙基-1H-吡唑-4-基)嘧啶-2-胺(420mg,1.9mmol)中添加HBr(5mL，48％水溶液)。将反应混合物加热至100℃，并且在所述温度下搅拌2h。浓缩反应混合物，然后添加POCl3(5mL)。将反应混合物加热至100℃，并且在所述温度下搅拌16h。将反应混合物冷却至室温并倾倒至冰水中。用NaOH水溶液(5M)将溶液的pH调整至pH＝8。用EtOAc(2×30mL)萃取碱性水相。将合并的有机层用盐水(100mL)洗涤，干燥(Na2SO4)，并且浓缩。将粗物质通过硅胶色谱法(PE:EtOAc＝1:1)纯化，以得到呈白色固体的4-氯-N-(1-乙基-1H-吡唑-4-基)嘧啶-2-胺(220mg，产率：51％)。ESI-MS(M+H)+:224.1。HBr (5 mL, 48% aqueous solution) was added to 4-methoxy-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (420 mg, 1.9 mmol). The reaction mixture was heated to 100 ° C and stirred at the temperature for 2 h. The reaction mixture was concentrated and POCl 3 (5 mL) was added. The reaction mixture was heated to 100 ° C and stirred at the temperature for 16 h. The reaction mixture was cooled to room temperature and poured into ice water. The pH of the solution was adjusted to pH=8 with aqueous NaOH solution (5 M). The basic aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (100 mL), dried (Na 2 SO 4 ), and concentrated. The crude material was purified by silica gel chromatography (PE: EtOAc=1: 1) to give 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (220 mg, yield: 51%) as a white solid. ESI-MS (M+H) + : 224.1.

3. 5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成3. 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在N2下向8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(560mg,1.13mmol)和PinB-BPin(288mg,1.10mmol)于无水1,4-二噁烷(11mL)中的混合物中快速添加KOAc(332mg,3.39mmol)和Pd(dppf)Cl2·CH2Cl2(89mg,0.11mmol)。在100℃、N2下将混合物搅拌12h。冷却之后，添加4-氯-N-(1-乙基-1H-吡唑-4-基)嘧啶-2-胺(301mg,1.35mmol)、K2CO3(312mg,2.26mmol)、Pd(dppf)Cl2·CH2Cl2(89mg,0.11mmol)和H2O(2.5mL)。在80℃、N2下将混合物搅拌2h。冷却之后，将混合物浓缩并通过硅胶柱(PE:EtOAc＝3:1)纯化，以得到呈黄色固体的5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(200mg，产率：29％)。ESI-MS(M+H)+:602.2。8-Bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was added under N2 To a mixture of tert-butyl-2-carboxylate (560 mg, 1.13 mmol) and PinB-BPin (288 mg, 1.10 mmol) in anhydrous 1,4-dioxane (11 mL) were quickly added KOAc (332 mg, 3.39 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (89 mg, 0.11 mmol). The mixture was stirred at 100° C. under N 2 for 12 h. After cooling, 4-chloro-N-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-amine (301 mg, 1.35 mmol), K 2 CO 3 (312 mg, 2.26 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (89 mg, 0.11 mmol) and H 2 O (2.5 mL) were added. The mixture was stirred at 80° C. under N 2 for 2 h. After cooling, the mixture was concentrated and purified by silica gel column (PE:EtOAc=3:1) to give 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (200 mg, yield: 29%). ESI-MS (M+H) + : 602.2.

4. 5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的制备4. 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

向5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(200mg,0.33mmol)于CH2Cl2(5mL)中的溶液中添加TFA(5mL)，在室温下将混合物搅拌1h。浓缩之后，将粗产物(166mg，产率：100％)用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:502.7。5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine To a solution of tert-butyl-2-carboxylate (200 mg, 0.33 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 mL), and the mixture was stirred at room temperature for 1 h. After concentration, the crude product (166 mg, yield: 100%) was used in the next step without further purification. ESI-MS (M+H) + : 502.7.

5. 5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺(I-RP1)的合成5. 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-(5-yl)-1,2,4-oxadiazole-3-carboxamide (I-RP1)

向5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(166mg,0.33mmol)和二氢呋喃-3(2H)-酮(119mg,1.65mmol)于MeOH(18mL)中的溶液中添加NaBH3CN(21mg,0.33mmol)和ZnCl2(90mg,0.66mmol)。在室温下将混合物搅拌3h。浓缩并用水(30mL)稀释之后，用EtOAc(80mL×2)萃取混合物。将合并的有机层用H2O(60mL)洗涤并浓缩。将粗产物通过制备型TLC(CH2Cl2:MeOH＝20:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(60mg，产率：32％)。ESI-MS(M+H)+:557.7。1H NMR(400MHz,CDCl3)δ:8.42(d,J＝5.2Hz,2H),7.90(s,1H),7.85(d,J＝8.0Hz,1H),7.79(s,1H),7.57-7.53(m,2H),7.04(d,J＝5.2Hz,1H),5.71(t,J＝8.4Hz,1H),4.82-4.66(m,4H),4.17(q,J＝7.2Hz,2H),3.91-3.72(m,3H),2.99-2.92(m,1H),2.63-2.58(m,1H),2.40-2.34(m,1H),2.15-2.07(m,1H),1.51(t,J＝7.6Hz,3H),1.45(s,9H)。To 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1,2,4-oxadiazole-3-carboxamide (166 mg, 0.33 mmol) and dihydrofuran-3(2H)-one (119 mg, 1.65 mmol) in MeOH (18 mL) were added NaBH 3 CN (21 mg, 0.33 mmol) and ZnCl 2 (90 mg, 0.66 mmol). The mixture was stirred at room temperature for 3 h. After concentration and dilution with water (30 mL), the mixture was extracted with EtOAc (80 mL×2). The combined organic layers were washed with H 2 O (60 mL) and concentrated. The crude product was purified by preparative TLC ( CH2Cl2 : MeOH =20:1) to give 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (60 mg, yield: 32%). ESI-MS (M+H) + : 557.7. 1 H NMR (400 MHz, CDCl 3 )δ:8.42(d,J＝5.2Hz,2H),7.90(s,1H),7.85(d,J＝8.0Hz,1H),7.79(s,1H),7.57-7.53(m,2H),7.04(d,J＝5.2Hz,1H),5.71(t,J＝8.4Hz,1H),4.82-4.66 (m,4H),4.17(q,J＝7.2Hz,2H),3.91-3.72(m,3H),2.99-2.92(m,1H),2.63-2.58(m,1H),2.40-2.34(m,1H),2.15-2.07(m,1H),1.51(t,J＝7.6Hz,3H) ,1.45(s,9H).

实施例8. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物8)Example 8. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 8)

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例12步骤4中5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(20mg，产率：14％)。ESI-MS(M+H)+:572.3。1H NMR(400MHz,CD3OD)δ:8.30(s,1H),7.91-7.86(m,3H),7.53(s,1H),7.36(d,J＝8.0Hz,1H),7.10(d,J＝5.6Hz,1H),5.48(d,J＝9.2Hz,1H),4.19-3.88(m,4H),3.78(s,3H),3.30-3.21(m,2H),3.16-3.03(m,2H),2.67-2.62(m,1H),2.16-2.11(m,1H),1.96-1.83(m,3H),1.64-1.52(m,2H),1.38(s,9H)。5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in step 4 of Example 12 was similar. The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H- pyran -4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (20 mg, yield: 14%). ESI-MS (M+H) + : 572.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.30 (s, 1H), 7.91-7.86 (m, 3H), 7.53 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.10 (d, J = 5.6Hz, 1H), 5.48 (d, J = 9.2Hz, 1H), 4.19-3.88 (m, 4H),3.78(s,3H),3.30-3.21(m,2H),3.16-3.03(m,2H),2.67-2.62(m,1H),2.16-2.11(m,1H),1.96-1.83(m,3H),1.64-1.52(m,2H),1.38(s,9H).

实施例9.(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物9)Example 9. (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 9)

1.(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在90℃、氮气下将(R)-8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.2g,2.43mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂硼杂环戊烷)(650mg,2.56mmol)、KOAc(477mg,4.86mmol)和Pd(dppf)Cl2.DCM(196mg,0.24mmol)于30mL 1,4-二噁烷中的混合物搅拌2h。冷却至室温之后，将混合物用EtOAc(200mL)稀释，用水(50mL×2)洗涤，用Na2SO4干燥并浓缩，以得到(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯，其用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:541.3。(R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was reacted at 90°C under nitrogen. A mixture of tert-butyl-2-carboxylate (1.2 g, 2.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (650 mg, 2.56 mmol), KOAc (477 mg, 4.86 mmol) and Pd(dppf)Cl 2 .DCM (196 mg, 0.24 mmol) in 30 mL 1,4-dioxane was stirred for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with water (50 mL×2), dried over Na 2 SO 4 and concentrated to give (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester, which was used in the next step without further purification. ESI-MS (M+H) + : 541.3.

2.(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-氯嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成2. (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在90℃、N2气氛下将(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.31g,2.43mmol)、2,4-二氯嘧啶(344mg,2.31mmol)、Pd(dppf)Cl2(196mg,0.24mmol)和K2CO3(672mg,4.86mmol)于20mL二噁烷/H2O(4:1)中的混合物搅拌12h。移除溶剂之后，将残余物通过硅胶色谱法(CH2Cl2:MeOH＝20:1)纯化，以得到呈黄色固体的(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-氯嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(900mg，产率：70％(两个步骤))。ESI-MS(M+H)+:527.2。(R)-5-(5-(tert- butyl )-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was reacted at 90°C under N2 atmosphere. A mixture of tert-butyl-2-carboxylate (1.31 g, 2.43 mmol), 2,4-dichloropyrimidine (344 mg, 2.31 mmol), Pd(dppf)Cl 2 (196 mg, 0.24 mmol) and K 2 CO 3 (672 mg, 4.86 mmol) in 20 mL of dioxane/H 2 O (4:1) was stirred for 12 h. After removing the solvent, the residue was purified by silica gel chromatography (CH 2 Cl 2 :MeOH=20:1) to give (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (900 mg, yield: 70% (two steps)). ESI-MS (M+H) + : 527.2.

3.(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成3. (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在100℃、氮气下将(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-氯嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(900mg,1.71mmol)、1,5-二甲基-1H-吡唑-4-胺(228mg,2.05mmol)、Cs2CO3(1.11g,3.42mmol)、Pd2(dba)3(157mg,0.17mmol)和S-Phos(140mg,0.34mmol)于15mL 1,4-二噁烷中的混合物搅拌2h。将混合物用EtOAc(200mL)稀释并用水(60mL×2)洗涤。将有机相用Na2SO4干燥并浓缩。将粗产物通过硅胶色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(110mg，产率：11％)。ESI-MS(M+H)+:602.3。1H NMR(400MHz,CDCl3)δ:8.39-8.38(m,1H),7.93-7.90(m,2H),7.67(s,1H),7.46-7.44(m,2H),7.05(d,J＝4.2Hz,1H),6.48-6.41(m,1H),5.69-5.59(m,1H),4.81-4.66(m,1H),4.50-4.41(m,1H),4.10-4.03(m,1H),3.81(s,3H),3.61-3.52(m,1H),2.23(s,3H),2.20-2.16(m,2H),1.40(s,9H),1.34-1.30(m,9H)。(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was reacted at 100°C under nitrogen. A mixture of tert-butyl-2-carboxylate (900 mg, 1.71 mmol), 1,5-dimethyl-1H-pyrazol-4-amine (228 mg, 2.05 mmol), Cs 2 CO 3 (1.11 g, 3.42 mmol), Pd 2 (dba) 3 (157 mg, 0.17 mmol) and S-Phos (140 mg, 0.34 mmol) in 15 mL of 1,4-dioxane was stirred for 2 h. The mixture was diluted with EtOAc (200 mL) and washed with water (60 mL×2). The organic phase was dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel chromatography (DCM/MeOH=20:1) to give (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (110 mg, yield: 11%). ESI-MS (M+H) + : 602.3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.39-8.38 (m, 1H), 7.93-7.90 (m, 2H), 7.67 (s, 1H), 7.46-7.44 (m, 2H), 7.05 (d, J = 4.2Hz, 1H), 6.48-6.41 (m, 1H), 5.69-5.59 (m, 1H),4.81-4.66(m,1H),4.50-4.41(m,1H),4.10-4.03(m,1H),3.81(s,3H),3.61-3.52(m,1H),2.23(s,3H),2.20-2.16(m,2H),1.40(s,9H),1.34- 1.30(m,9H).

4.(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的合成4. (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例2中5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗物质向下进行而无需进一步纯化。ESI-MS(M+H)+:502.2。(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in Example 2 was similar to that of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 4-(5-yl)-1,2,4-oxadiazole-3-carboxamide. The crude material was carried forward without further purification. ESI-MS (M+H) + : 502.2.

5.(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的合成5. (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例3中5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗物质通过硅胶色谱法(CH2Cl2:MeOH＝10:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2-羟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(43mg，产率42％)。ESI-MS(M+H)+:546.3。1HNMR(400MHz,CD3OD)δ:8.32(d,J＝5.2Hz,1H),8.00-7.98(m,2H),7.60(s,1H),7.42(d,J＝8.0Hz,1H),7.23(d,J＝5.2Hz,1H),5.58-5.56(m,1H),4.16-4.10(m,2H),3.82(s,3H),3.73(t,J＝6.0Hz,2H),3.30-3.21(m,2H),2.67-2.65(m,2H),2.30-2.27(m,1H),2.25(s,3H),2.02-1.96(m,1H),1.52(s,9H)。(R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that in Example 3. The crude material was purified by silica gel chromatography (CH 2 Cl 2 :MeOH=10:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (43 mg, yield 42%). ESI-MS (M+H) + : 546.3. 1 HNMR(400MHz,CD 3 OD)δ:8.32(d,J＝5.2Hz,1H),8.00-7.98(m,2H),7.60(s,1H),7.42(d,J＝8.0Hz,1H),7.23(d,J＝5.2Hz,1H),5.58-5.56(m,1H),4.16-4.10(m,2H),3.82(s,3H),3.73(t,J＝6.0Hz,2H),3.30-3.21(m,2H),2.67-2.65(m,2H),2.30-2.27(m,1H),2.25(s,3H),2.02-1.96(m,1H),1.52(s,9H)。

实施例10. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物10)Example 10. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 10)

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例7步骤3中所述的合成。将粗物质通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(97mg，产率：57％)。ESI-MS(M+H)+:558.3。1H NMR(400MHz,CD3OD)δ:8.43(d,J＝5.2Hz,1H),8.04-7.99(m,3H),7.64-7.63(m,1H),7.48(d,J＝8.0Hz,1H),7.24(d,J＝5.2Hz,1H),5.61(d,J＝9.6Hz,1H),4.10-3.91(m,4H),3.90(s,3H),3.78-3.71(m,2H),3.36-3.10(m,3H),2.33-2.20(m,2H),2.06-1.96(m,2H),1.52(s,9H)。5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-( 2 -((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4 -yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that described in Example 7, Step 3. The crude material was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to give 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (97 mg, yield: 57%). ESI-MS (M+H) + : 558.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.43 (d, J = 5.2 Hz, 1H), 8.04-7.99 (m, 3H), 7.64-7.63 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 5.61 (d, J = 9.6 Hz, 1H) ),4.10-3.91(m,4H),3.90(s,3H),3.78-3.71(m,2H),3.36-3.10(m,3H),2.33-2.20(m,2H),2.06-1.96(m,2H),1.52(s,9H).

实施例11.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物11)Example 11. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 11)

1.(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于实施例1步骤12中1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯的合成。将粗物质通过硅胶色谱法(EtOAc:MeOH＝15:1)纯化，以得到呈黄色固体的(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.5g，产率：43％)。ESI-MS(M+H)+:588.3。(R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that of 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine in step 12 of Example 1. -3-(2H)-carboxylic acid tert-butyl ester. The crude material was purified by silica gel chromatography (EtOAc:MeOH=15:1) to give (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (1.5 g, yield: 43%). ESI-MS (M+H) + : 588.3.

2.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的合成2. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

向(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.4g,2.3mmol)于CH2Cl2(10mL)中的溶液中添加TFA(10mL)。在室温下将混合物搅拌1h。将反应混合物浓缩并将粗产物(1.0g，产率：81％)用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:488.3。To (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine To a solution of tert-butyl-2-carboxylate (1.4 g, 2.3 mmol) in CH 2 Cl 2 (10 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated and the crude product (1.0 g, yield: 81%) was used in the next step without further purification. ESI-MS (M+H) + : 488.3.

3.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,2,4-噁二唑-3-甲酰胺的合成3. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,2,4-oxadiazole-3-carboxamide

向(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(75mg,0.15mmol)于CH3CN(5mL)中的溶液中添加三氟甲烷磺酸2,2,2-三氟乙酯(60mg,0.3mmol)和DIPEA(34mg,0.3mmol)。在80℃、微波下将混合物搅拌2h。将混合物浓缩并通过制备型TLC(DCM/MeOH＝10:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺(45mg，产率：58％)。ESI-MS(M+H)+:570.2。1H NMR(400MHz,CD3OD)δ:8.30(d,J＝5.6Hz,1H),7.92-7.86(m,3H),7.50(s,1H),7.35(d,J＝8.0Hz,1H),7.10(d,J＝5.6Hz,1H),5.48-5.50(m,1H),4.26-4.22(m,1H),4.02-3.98(m,1H),3.78(s,3H),3.32-3.27(m,1H),3.21-3.17(m,1H),3.05-2.98(m,2H),2.17-2.07(m,1H),1.91-1.82(m,1H),1.40(s,9H)。To (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of (R)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (75 mg, 0.15 mmol) in CH 3 CN (5 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (60 mg, 0.3 mmol) and DIPEA (34 mg, 0.3 mmol). The mixture was stirred at 80° C. under microwave for 2 h. The mixture was concentrated and purified by preparative TLC (DCM/MeOH=10:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,2,4-oxadiazole-3-carboxamide (45 mg, yield: 58%). ESI-MS (M+H) + : 570.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.30 (d, J = 5.6Hz, 1H), 7.92-7.86 (m, 3H), 7.50 (s, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.10 (d, J = 5.6Hz, 1H), 5.48-5.50 (m, 1H), 4.26-4. 22(m,1H),4.02-3.98(m,1H),3.78(s,3H),3.32-3.27(m,1H),3.21-3.17(m,1H),3.05-2.98(m,2H),2.17-2.07(m,1H),1.91-1.82(m,1H),1.40(s,9 H).

实施例12. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物12)Example 12. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 12)

1. 8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂2(3H)-羧酸叔丁酯的制备1. 8-Bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine Preparation of tert-butyl 2(3H)-carboxylate

向5-(叔丁基)-1,3,4-噁二唑-2-羧酸钾(1.4g,6.7mmol)和HATU(3.2g,8.4mmol)于DMF(20mL)中的溶液中添加三乙胺(1.69g,16.8mmol)和5-氨基-8-溴-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(1.9g,5.6mmol)。在室温下将混合物搅拌4h。用水(80mL)稀释之后，用EtOAc(100mL×2)萃取混合物。将合并的有机物用盐水(80mL)洗涤，干燥并浓缩。将粗产物通过硅胶柱色谱法(PE/EtOAc＝2:1)纯化，以得到呈黄色固体的8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(1.8g，产率：62％)。ESI-MS(M+H-56)+:437.3。1H NMR(400MHz,CD3OD)δ:7.51-7.43(m,2H),7.28-7.26(m,1H),5.52-5.45(m,1H),4.65-4.61(m,1H),4.43-4.39(m,1H),4.15-4.09(m,1H),3.65-3.43(m,1H),2.08-2.03(m,2H),1.50(s,9H),1.43-1.42(m,9H)。To a solution of potassium 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (1.4 g, 6.7 mmol) and HATU (3.2 g, 8.4 mmol) in DMF (20 mL) were added triethylamine (1.69 g, 16.8 mmol) and 5-amino-8-bromo-4,5-dihydro-1H-benzo[c]azepine. -2 (3H) -carboxylic acid tert-butyl ester (1.9g, 5.6mmol). The mixture was stirred at room temperature for 4h. After dilution with water (80mL), the mixture was extracted with EtOAc (100mL×2). The combined organics were washed with brine (80mL), dried and concentrated. The crude product was purified by silica gel column chromatography (PE/EtOAc=2:1) to give 8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-formylamino)-4,5-dihydro-1H-benzo[c]azepine as a yellow solid. -2(3H)-carboxylic acid tert-butyl ester (1.8 g, yield: 62%). ESI-MS (M+H-56) + : 437.3. 1 H NMR (400 MHz, CD 3 OD) δ: 7.51-7.43 (m, 2H), 7.28-7.26 (m, 1H), 5.52-5.45 (m, 1H), 4.65-4.61 (m, 1H), 4.43-4.39 (m, 1H), 4.15-4.09 (m, 1H), 3.65-3.43 (m, 1H), 2.08-2.03 (m, 2H), 1.50 (s, 9H), 1.43-1.42 (m, 9H).

2. 5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂2(3H)-羧酸叔丁酯的制备2. 5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine Preparation of tert-butyl 2(3H)-carboxylate

在80℃、氮气下将8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(1.6g,3.2mmol)、PinB-BPin(802mg,3.84mmol)、KOAc(640mg,6.4mmol)和Pd(dppf)Cl2·CH2Cl2(130mg,0.16mmol)于20mL无水1,4-二噁烷中的混合物搅拌16h。将混合物冷却至室温之后，添加4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(802mg,3.84mmol)、Pd(dppf)Cl2·CH2Cl2(130mg,0.16mmol)、K2CO3(1.3g,9.6mmol)和H2O(5mL)，并且在80℃下将所得混合物再搅拌16h。将混合物用EtOAc(200mL)稀释，用水(80mL×2)洗涤，用Na2SO4干燥并浓缩。将粗产物通过硅胶柱色谱法(EtOAc/MeOH＝20:1)纯化，以得到呈黄色固体的5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(1.4g，产率：86％)。ESI-MS(M+H)+:588.3。1H NMR(400MHz,CD3OD)δ:8.42-8.38(m,1H),8.11-7.95(m,3H),7.66-7.50(m,2H),7.24-7.21(m,1H),5.64-5.62(m,1H),4.85-4.47(m,2H),3.93-3.88(m,1H),3.57-3.54(m,1H),2.12-2.10(m,2H),1.51(s,9H),1.43-1.34(m,9H)8-Bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine was added under nitrogen at 80°C. A mixture of tert-butyl-2(3H)-carboxylate (1.6 g, 3.2 mmol), PinB-BPin (802 mg, 3.84 mmol), KOAc (640 mg, 6.4 mmol) and Pd(dppf)Cl 2 ·CH 2 Cl 2 (130 mg, 0.16 mmol) in 20 mL of anhydrous 1,4-dioxane was stirred for 16 h. After the mixture was cooled to room temperature, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (802 mg, 3.84 mmol), Pd(dppf)Cl 2 ·CH 2 Cl 2 (130 mg, 0.16 mmol), K 2 CO 3 (1.3 g, 9.6 mmol) and H 2 O (5 mL) were added, and the resulting mixture was stirred at 80° C. for another 16 h. The mixture was diluted with EtOAc (200 mL), washed with water (80 mL×2), dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/MeOH=20:1) to give 5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine as a yellow solid. -2(3H)-carboxylic acid tert-butyl ester (1.4 g, yield: 86%). ESI-MS (M+H) + :588.3. 1 H NMR (400 MHz, CD 3 OD) δ:8.42-8.38 (m, 1H), 8.11-7.95 (m, 3H), 7.66-7.50 (m, 2H), 7.24-7.21 (m, 1H), 5.64-5.62 (m, 1H), 4.85-4.47 (m, 2H), 3.93-3.88 (m, 1H), 3.57-3.54 (m, 1H), 2.12-2.10 (m, 2H), 1.51 (s, 9H), 1.43-1.34 (m, 9H)

3. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺的制备3. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-methyl)-1,3,4-oxadiazole-2-carboxamide

向5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯(600mg,1.02mmol)于CH2Cl2(5mL)中的溶液中添加TFA(5mL)。在室温下将混合物搅拌1h。移除溶剂之后，将残余物在真空中干燥，以得到粗标题产物(460mg，产率：80％)，其用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:488.3。To 5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine To a solution of tert-butyl-2(3H)-carboxylate (600 mg, 1.02 mmol) in CH 2 Cl 2 (5 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 1 h. After removing the solvent, the residue was dried in vacuo to give the crude title product (460 mg, yield: 80%), which was used in the next step without further purification. ESI-MS (M+H) + : 488.3.

4. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成4. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 1,3,4-oxadiazole-2-carboxamide

向5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(170mg,0.35mmol)和二氢-吡喃-4-酮(175mg,1.75mmol)于MeOH(30mL)中的溶液中添加NaBH3CN(112mg,1.75mmol)和CH3COOH(催化剂)。在50℃下将混合物搅拌4h。冷却至室温之后，用浓NH4OH将混合物调整至pH＝8。浓缩之后，将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(24mg，产率：9％)。ESI-MS(M+H)+:572.3。1H NMR(400MHz,CD3OD)δ:8.29(d,J＝5.2Hz,1H),7.91-7.85(m,3H),7.53(s,1H),7.36(d,J＝8.0Hz,1H),7.10(d,J＝5.6Hz,1H),5.44(d,J＝9.2Hz,1H),4.08-3.86(m,4H),3.78(s,3H),3.28-3.20(m,3H),3.08-3.01(m,1H),2.63-2.57(m,1H),2.14-2.09(m,1H),1.94-1.76(m,3H),1.63-1.49(m,2H),1.38(s,9H)。To 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1-(5-yl)-1,3,4-oxadiazole-2-carboxamide (170 mg, 0.35 mmol) and dihydro-pyran-4-one (175 mg, 1.75 mmol) in MeOH (30 mL) were added NaBH 3 CN (112 mg, 1.75 mmol) and CH 3 COOH (catalyst). The mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the mixture was adjusted to pH=8 with concentrated NH 4 OH. After concentration, the crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to give 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5- tetrahydro -1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (24 mg, yield: 9%). ESI-MS (M+H) + : 572.3. 1 H NMR(400MHz,CD 3 OD)δ:8.29(d,J＝5.2Hz,1H),7.91-7.85(m,3H),7.53(s,1H),7.36(d,J＝8.0Hz,1H),7.10(d,J＝5.6Hz,1H),5.44(d,J＝9.2Hz,1H),4.08-3.86(m,4H),3.78(s,3H),3.28-3.20(m,3H),3.08-3.01(m,1H),2.63-2.57(m,1H),2.14-2.09(m,1H),1.94-1.76(m,3H),1.63-1.49(m,2H),1.38(s,9H)。

实施例13. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物13)Example 13. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 13)

5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成类似于实施例8中5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(四氢-2H-吡喃-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(59mg，产率：33％)。ESI-MS(M+H)+:544.2。1H NMR(400MHz,CD3OD)δ:8.29(d,J＝5.2Hz,1H),7.91(d,J＝8.0Hz,1H),7.86(s,1H),7.83(s,1H),7.51(s,1H),7.36(d,J＝8.4Hz,1H),7.09(d,J＝5.2Hz,1H),5.46(d,J＝10.0Hz,1H),4.65-5.55(m,4H),3.83-3.67(m,3H),3.77(s,3H),2.96-2.93(m,1H),2.79-2.73(m,1H),2.13-2.10(m,1H),1.93-1.90(m,1H),1.38(s,9H)。5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in Example 8 was similar. The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H- benzo [c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (59 mg, yield: 33%). ESI-MS (M+H) + : 544.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.29 (d, J = 5.2Hz, 1H), 7.91 (d, J = 8.0Hz, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.36 (d, J = 8.4Hz, 1H), 7.09 (d, J = 5.2Hz, 1H) ),5.46(d,J＝10.0Hz,1H),4.65-5.55(m,4H),3.83-3.67(m,3H),3.77(s,3H),2.96-2.93(m,1H),2.79-2.73(m,1H),2.13-2.10(m,1H),1.93-1.90 (m,1H),1.38(s,9H).

实施例14.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物14a)和(S)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物14b)Example 14. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 14a) and (S)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 14b)

方法1Method 1

使5-叔丁基-1,3,4-噁二唑-2-羧酸{8-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2-氧杂环丁烷-3-基-2,3,4,5-四氢-1H-2-苯并氮杂-5-基}-酰胺(264mg)经历SFC分离(OD-H(2×25cm)，30％甲醇(0.1％DEA)/CO2，100巴，65mL/min，220nm，注射体积：0.5mL，4mg/mL，甲醇)并产生93mg峰1(化学纯度>99％，ee>99％)和97mg峰2(化学纯度>99％，ee>99％)。5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid {8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepine -5-yl}-amide (264 mg) was subjected to SFC separation (OD-H (2×25 cm), 30% methanol (0.1% DEA)/CO 2 , 100 bar, 65 mL/min, 220 nm, injection volume: 0.5 mL, 4 mg/mL, methanol) and produced 93 mg of peak 1 (chemical purity>99%, ee>99%) and 97 mg of peak 2 (chemical purity>99%, ee>99%).

峰1被指定为5-叔丁基-1,3,4-噁二唑-2-羧酸{(R)-8-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2-氧杂环丁烷-3-基-2,3,4,5-四氢-1H-2-苯并氮杂-5-基}-酰胺：LCMS:Rt 0.84min，m/z 544.2。1H NMR(400MHz,甲醇-d4)δ8.41(br.s.,1H),7.84-8.14(m,3H),7.63(br.s.,1H),7.47(t,J＝7.56Hz,1H),7.21(d,J＝10.04Hz,1H),5.57(d,J＝9.29Hz,1H),4.61-4.80(m,4H),3.66-4.07(m,6H),3.05(br.s.,1H),2.88(d,J＝9.04Hz,1H),2.23(br.s.,1H),2.05(br.s.,1H),1.50(d,J＝2.89Hz,9H)。Peak 1 was assigned to 5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid {(R)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepine -5-yl}-amide: LCMS: Rt 0.84 min, m/z 544.2. 1 H NMR (400MHz, methanol-d 4 ) δ8.41 (br.s., 1H), 7.84-8.14 (m, 3H), 7.63 (br.s., 1H), 7.47 (t, J = 7.56Hz, 1H), 7.21 (d, J = 10.04Hz, 1H), 5.57 (d, J = 9.29Hz, 1H), 4. 61-4.80(m,4H),3.66-4.07(m,6H),3.05(br.s.,1H),2.88(d,J＝9.04Hz,1H),2.23(br.s.,1H),2.05(br.s.,1H),1.50(d,J＝2.89Hz,9H).

峰2被指定为5-叔丁基-1,3,4-噁二唑-2-羧酸{(S)-8-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2-氧杂环丁烷-3-基-2,3,4,5-四氢-1H-2-苯并氮杂-5-基}-酰胺:LCMS:Rt 0.84min，m/z 544.2。1H NMR(400MHz,甲醇-d4)δ8.42(d,J＝5.02Hz,1H),7.86-8.14(m,3H),7.63(s,1H),7.48(d,J＝8.09Hz,1H),7.22(d,J＝5.27Hz,1H),5.58(d,J＝9.73Hz,1H),4.59-4.81(m,4H),3.73-4.05(m,6H),3.05(br.s.,1H),2.89(br.s.,1H),2.23(br.s.,1H),2.06(d,J＝5.52Hz,1H),1.50(s,9H)。Peak 2 was assigned to 5-tert-butyl-1,3,4-oxadiazole-2-carboxylic acid {(S)-8-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-2-oxetan-3-yl-2,3,4,5-tetrahydro-1H-2-benzazepine -5-yl}-amide: LCMS: Rt 0.84 min, m/z 544.2. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.42 (d, J=5.02 Hz, 1H), 7.86-8.14 (m, 3H), 7.63 (s, 1H), 7.48 (d, J=8.09 Hz, 1H), 7.22 (d, J=5.27 Hz, 1H), 5.58 (d, J=9.73 Hz, 1H), 4.59-4.81 (m, 4H), 3.73-4.05 (m, 6H), 3.05 (br. s., 1H), 2.89 (br. s., 1H), 2.23 (br. s., 1H), 2.06 (d, J=5.52 Hz, 1H), 1.50 (s, 9H).

方法2Method 2

1.(R)-8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-8-Bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

向(R)-5-氨基-8-溴-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.1g,4.5mmol)和三乙胺(910mg,9.0mmol)于DCM(100mL)中的溶液中添加HATU(2.6g,6.8mmol)和5-(叔丁基)-1,3,4-噁二唑-2-羧酸钾(1.12g,5.4mmol)。在室温下将混合物搅拌2h。然后添加水(100mL)并用DCM(2×100mL)萃取混合物。将合并的有机物干燥且浓缩。将粗产物通过硅胶柱色谱法(石油醚/EtOAc＝4:1)纯化，以得到呈白色固体的(R)-8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.8g，产率：82％)。ESI-MS(M+H)+:493.1。To (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (3.1g, 4.5mmol) and triethylamine (910mg, 9.0mmol) in DCM (100mL) solution were added HATU (2.6g, 6.8mmol) and 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate potassium (1.12g, 5.4mmol). The mixture was stirred at room temperature for 2h. Water (100mL) was then added and the mixture was extracted with DCM (2×100mL). The combined organics were dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to obtain (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a white solid. -2-carboxylic acid tert-butyl ester (1.8 g, yield: 82%). ESI-MS (M+H) + : 493.1.

2.(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成2. (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在90℃、氮气下将(R)-8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.8g,3.65mmol)、双(频那醇)二硼(975mg,3.84mmol)、KOAc(715mg,7.30mmol)和Pd(dppf)Cl2.DCM(293mg,0.36mmol)于30mL 1,4-二噁烷中的混合物搅拌2h。冷却至室温之后，将混合物用EtOAc(200mL)稀释，用水(2×50mL)洗涤，用Na2SO4干燥并浓缩。将粗产物(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯用于下一步骤而无需纯化。ESI-MS(M+H)+:541.3。(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was reacted at 90°C under nitrogen. A mixture of tert-butyl-2-carboxylate (1.8 g, 3.65 mmol), bis(pinacolato)diboron (975 mg, 3.84 mmol), KOAc (715 mg, 7.30 mmol) and Pd(dppf)Cl 2 .DCM (293 mg, 0.36 mmol) in 30 mL of 1,4-dioxane was stirred for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), dried over Na 2 SO 4 and concentrated. The crude product (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was obtained. -2-carboxylic acid tert-butyl ester was used in the next step without purification. ESI-MS (M+H) + : 541.3.

3.(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成3. (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

将(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(4.85g,8.98mmol)、4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(1.88g,8.98mmol)、Pd(dppf)Cl2(734mg,0.9mmol)和K2CO3(2.48g,18mmol)于二噁烷/H2O(4:1,20mL)中的混合物除气并在100℃、N2气氛下搅拌2h。浓缩反应混合物之后，将残余物通过硅胶色谱法(EtOAc:PE＝2:1)纯化，以产生呈黄色固体的(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.4g，产率：51％)。ESI-MS(M+H)+:588.3。(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine A mixture of tert-butyl-2-carboxylate (4.85 g, 8.98 mmol), 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.88 g, 8.98 mmol), Pd(dppf)Cl 2 (734 mg, 0.9 mmol) and K 2 CO 3 (2.48 g, 18 mmol) in dioxane/H 2 O (4:1, 20 mL) was degassed and stirred at 100 °C under N 2 atmosphere for 2 h. After the reaction mixture was concentrated, the residue was purified by silica gel chromatography (EtOAc:PE=2:1) to give (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (3.4 g, yield: 51%). ESI-MS (M+H) + : 588.3.

4.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺的合成4. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,3,4-oxadiazole-2-carboxamide

向(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.4g,5.79mmol)于DCM(10mL)中的溶液中添加TFA(4mL)。在室温下将所得溶液搅拌2h。浓缩反应混合物之后，将残余物溶解于MeOH(10mL)中并用氨水调整至pH＝8。然后添加水(20mL)并用DCM/MeOH溶液(20:1,30mL×3)萃取混合物。将有机相干燥并浓缩，以得到呈黄色固体的粗(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(2.47g，产率：88％)，其用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:488.2。To (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (3.4g, 5.79mmol) was added to a solution of DCM (10mL) with TFA (4mL). The resulting solution was stirred at room temperature for 2h. After the reaction mixture was concentrated, the residue was dissolved in MeOH (10mL) and adjusted to pH=8 with ammonia. Water (20mL) was then added and the mixture was extracted with DCM/MeOH solution (20:1, 30mL×3). The organic phase was dried and concentrated to give a crude (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (2.47 g, yield: 88%), which was used in the next step without further purification. ESI-MS (M+H) + : 488.2.

5.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺(I-RP38)的合成5. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-amino-1,3,4-oxadiazole-2-carboxamide (I-RP38)

向(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(1.5g,3.08mmol)和氧杂环丁烷-3-酮(1.1g,15.4mmol)于MeOH(30mL)中的溶液中添加NaBH3CN(970mg,15.4mmol)和ZnCl2(4.2g,30.8mmol)。在室温下将所得混合物搅拌4h。用H2O(20mL)稀释之后，用DCM/MeOH溶液(20:1,20mL×3)萃取混合物。将合并的有机层干燥并浓缩。将残余物通过硅胶色谱法(DCM:MeOH＝50:1至20:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(1.1g，产率：58％)。ESI-MS(M+H)+:544.3。1H NMR(400MHz,CDCl3)δ:8.42(d,J＝5.2Hz,1H),8.32(br,1H),7.86-7.78(m,3H),7.53-7.26(m,2H),7.15(s,1H),7.05-7.03(m,1H),5.62(t,J＝8.4Hz,1H),4.75-4.67(m,4H),3.94-3.85(m,6H),3.02-2.96(m,1H),2.75-2.70(m,1H),2.35-2.31(m,1H),2.14-2.07(m,1H),1.47(s,9H)。To (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1,4-dioxadiazole-2-carboxamide (1.5 g, 3.08 mmol) and oxetan-3-one (1.1 g, 15.4 mmol) in MeOH (30 mL) were added NaBH 3 CN (970 mg, 15.4 mmol) and ZnCl 2 (4.2 g, 30.8 mmol). The resulting mixture was stirred at room temperature for 4 h. After dilution with H 2 O (20 mL), the mixture was extracted with DCM/MeOH solution (20:1, 20 mL×3). The combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography (DCM:MeOH=50:1 to 20:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (1.1 g, yield: 58%). ESI-MS (M+H) + : 544.3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.42 (d, J = 5.2Hz, 1H), 8.32 (br, 1H), 7.86-7.78 (m, 3H), 7.53-7.26 (m, 2H), 7.15 (s, 1H), 7.05-7.03 (m, 1H), 5.62 (t, J = 8.4Hz, 1H) ),4.75-4.67(m,4H),3.94-3.85(m,6H),3.02-2.96(m,1H),2.75-2.70(m,1H),2.35-2.31(m,1H),2.14-2.07(m,1H),1.47(s,9H).

实施例15. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物15)Example 15. 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 15)

向5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(100mg,0.20mmol)于CH2Cl2(20mL)中的溶液中添加MsCl(34mg,0.3mmol)和三乙胺(61mg,0.60mmol)。在室温下将混合物搅拌2h。将混合物用CH2Cl2(100mL)稀释，用盐水(60mL)洗涤，并且浓缩。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(甲基磺酰基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(130mg，产率：87％)。ESI-MS(M+H)+:566.3。1H NMR(400MHz,DMSO-d6)δ:10.01(d,J＝7.6Hz,1H),9.57(s,1H),8.49(d,J＝5.2Hz,1H),8.07(s,1H),8.04(d,J＝8.4Hz,1H),7.99(br,1H),7.50(s,1H),7.47(d,J＝8.4Hz,1H),7.27(d,J＝5.2Hz,1H),5.56-5.51(m,1H),4.75-4.70(m,1H),4.60-4.56(m,1H),3.86-3.84(m,1H),3.83(s,3H),3.61-3.58(m,1H),2.80(s,3H),2.15-2.09(m,2H),1.43(s,9H)。To 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 5-(tert-butyl)-N-(8-(2-( ( 1 - methyl- 1H -pyrazol- 4 -yl ) amino)pyrimidin- 4 -yl)-2-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine ( ... -5-yl)-1,3,4-oxadiazole-2-carboxamide (130 mg, yield: 87%). ESI-MS (M+H) + : 566.3. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 10.01 (d, J = 7.6 Hz, 1H), 9.57 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.07 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.99 (br, 1H), 7.50 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 5. 2Hz,1H),5.56-5.51(m,1H),4.75-4.70(m,1H),4.60-4.56(m,1H),3.86-3.84(m,1H),3.83(s,3H),3.61-3.58(m,1H),2.80(s,3H),2.15-2.09(m, 2H),1.43(s,9H).

实施例16.(R)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物16)Example 16. (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 16)

1.(R)-8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-8-Bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

向(R)-5-氨基-8-溴-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.1g,4.5mmol)和三乙胺(910mg,9.0mmol)于DCM(100mL)中的溶液中添加HATU(2.6g,6.8mmol)和5-(叔丁基)-1,3,4-噁二唑-2-羧酸钾(1.12g,5.4mmol)。在室温下将混合物搅拌2h。然后添加水(100mL)并用DCM(2×100mL)萃取混合物。将合并的有机物干燥并浓缩。将粗产物通过硅胶柱色谱法(石油醚/EtOAc＝4:1)纯化，以得到呈白色固体的(R)-8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.8g，产率：82％)。ESI-MS(M+H)+:493.1。To (R)-5-amino-8-bromo-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (3.1g, 4.5mmol) and triethylamine (910mg, 9.0mmol) in DCM (100mL) were added HATU (2.6g, 6.8mmol) and 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate potassium (1.12g, 5.4mmol). The mixture was stirred at room temperature for 2h. Water (100mL) was then added and the mixture was extracted with DCM (2×100mL). The combined organics were dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to obtain (R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-formylamino)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a white solid. -2-carboxylic acid tert-butyl ester (1.8 g, yield: 82%). ESI-MS (M+H) + : 493.1.

2.(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成2. (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在90℃、氮气下将(R)-8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.8g,3.65mmol)、双(频那醇)二硼(975mg,3.84mmol)、KOAc(715mg,7.30mmol)和Pd(dppf)Cl2.DCM(293mg,0.36mmol)于30mL 1,4-二噁烷中的混合物搅拌2h。冷却至室温之后，将混合物用EtOAc(200mL)稀释，用水(2×50mL)洗涤，用Na2SO4干燥并浓缩。将粗产物(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯用于下一步骤而无需纯化。ESI-MS(M+H)+:541.3。(R)-8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was reacted at 90°C under nitrogen. A mixture of tert-butyl-2-carboxylate (1.8 g, 3.65 mmol), bis(pinacolato)diboron (975 mg, 3.84 mmol), KOAc (715 mg, 7.30 mmol) and Pd(dppf)Cl 2 .DCM (293 mg, 0.36 mmol) in 30 mL of 1,4-dioxane was stirred for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc (200 mL), washed with water (2×50 mL), dried over Na 2 SO 4 and concentrated. The crude product (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was obtained. -2-carboxylic acid tert-butyl ester was used in the next step without purification. ESI-MS (M+H) + : 541.3.

3.(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-氯嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成3. (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-chloropyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

在90℃、氮气下将(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯、2,4-二氯嘧啶(648mg,4.38mmol)、K2CO3(1.0g,7.30mmol)和Pd(dppf)Cl2.DCM(293mg,0.36mmol)于30mL 1,4-二噁烷和6mL水中的混合物搅拌12h。将混合物用EtOAc(200mL)稀释并用水(2×60mL)洗涤。将有机相用Na2SO4干燥并浓缩。将粗产物通过硅胶柱色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-氯嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.3g，产率：67％(两个步骤))。ESI-MS(M+H)+:527.2。(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine was reacted at 90°C under nitrogen. -2-carboxylic acid tert-butyl ester, 2,4-dichloropyrimidine (648 mg, 4.38 mmol), K 2 CO 3 (1.0 g, 7.30 mmol) and Pd (dppf) Cl 2 .DCM (293 mg, 0.36 mmol) in 30 mL 1,4-dioxane and 6 mL water was stirred for 12 h. The mixture was diluted with EtOAc (200 mL) and washed with water (2×60 mL). The organic phase was dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to give (R) -5- (5- (tert-butyl) -1,3,4- oxadiazole-2-carboxamido) -8- (2-chloropyrimidin-4-yl) -1,3,4,5-tetrahydro-2H-benzo [c] azepine as a yellow solid. -tert-Butyl 2-carboxylate (1.3 g, yield: 67% (two steps)). ESI-MS (M+H) + : 527.2.

4.(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成4. (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成(实施例9，步骤3)。将粗产物通过硅胶柱色谱法(EtOAc/石油醚＝3:1)纯化，以得到呈黄色固体的(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(280mg，产率：78％)。ESI-MS(M+H)+:616.3。(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that of (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (Example 9, Step 3). The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether=3:1) to give (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (280 mg, yield: 78%). ESI-MS (M+H) + : 616.3.

5.(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺的合成5. (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,3,4-oxadiazole-2-carboxamide

(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成类似于(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成(实施例9，步骤4)。将呈黄色固体的粗(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(240mg)用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:516.3。(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid -5-yl)-1,3,4-oxadiazole-2-carboxamide (240 mg) was used in the next step without further purification. ESI-MS (M+H) + : 516.3.

6.(R)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺的合成6. (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,3,4-oxadiazole-2-carboxamide

向(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(240mg,0.47mmol)和2-碘乙醇(200mg,1.17mmol)于10mL CH3CN中的溶液中添加K2CO3(195mg,1.41mmol)。在80℃下将所得混合物搅拌24h。用H2O(20mL)稀释之后，用DCM/MeOH溶液(20:1,3×40mL)萃取混合物。将合并的有机层干燥(Na2SO4)并浓缩。将残余物通过制备型TLC(DCM/MeOH＝10:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(108mg，产率：42％)。ESI-MS(M+H)+:560.3。1H NMR(400MHz,CD3OD)δ:8.37(d,J＝5.2Hz,1H),8.03(s,1H),7.98-7.95(m,2H),7.66(s,1H),7.44(d,J＝8.4Hz,1H),7.17(d,J＝5.2Hz,1H),5.55(d,J＝9.6Hz,1H),4.54-4.37(m,1H),4.17-4.04(m,2H),3.71(t,J＝6.0Hz,2H),3.30-3.17(m,2H),2.29-2.25(m,2H),2.29-2.25(m,1H),1.99-1.95(m,1H),1.52(d,J＝6.4Hz,6H),1.49(s,9H)。To (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 2-(4-(4-(4-yl)-1,3,4-oxadiazole-2-carboxamide (240 mg, 0.47 mmol) and 2-iodoethanol (200 mg, 1.17 mmol) in 10 mL of CH 3 CN was added K 2 CO 3 (195 mg, 1.41 mmol). The resulting mixture was stirred at 80° C. for 24 h. After dilution with H 2 O (20 mL), the mixture was extracted with DCM/MeOH solution (20:1, 3×40 mL). The combined organic layers were dried (Na 2 SO 4 ) and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10:1) to give (R)-5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (108 mg, yield: 42%). ESI-MS (M+H) + : 560.3. 1 H NMR (400 MHz, CD 3 OD)δ:8.37(d,J＝5.2Hz,1H),8.03(s,1H),7.98-7.95(m,2H),7.66(s,1H),7.44(d,J＝8.4Hz,1H),7.17(d,J＝5.2Hz,1H),5.55(d,J＝9.6Hz,1H),4.54-4.3 7(m,1H),4.17-4.04(m,2H),3.71(t,J＝6.0Hz,2H),3.30-3.17(m,2H),2.29-2.25(m,2H),2.29-2.25(m,1H),1.99-1.95(m,1H),1.52(d,J＝6.4Hz,6H ),1.49(s,9H).

实施例17.(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物17)Example 17. (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 17)

在室温下将(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(220mg,0.43mmol)、氧杂环丁烷-3-酮(157mg,2.15mmol)、NaBH3CN(135mg,2.15mmol)和ZnCl2(585mg,4.30mmol)于10mL MeOH中的混合物搅拌16h。将混合物用EtOAc(150mL)稀释并用水(50mL×2)洗涤。将有机相用Na2SO4干燥并浓缩。将粗产物通过硅胶色谱法(DCM:MeOH＝15:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(146mg，产率：60％)。ESI-MS(M+H)+:572.3。1H NMR(400MHz,CDCl3)δ:8.42(d,J＝5.2Hz,1H),8.05-7.97(m,3H),7.67(s,1H),7.48(d,J＝8.0Hz,1H),7.22(d,J＝8.4Hz,1H),5.59-5.57(m,1H),4.87-4.66(m,4H),4.53-4.50(m,1H),3.98-3.81(m,3H),3.09-3.03(m,1H),2.92-2.86(m,1H),2.29-2.20(m,1H),2.07-2.03(m,1H),1.54-1.51(m,15H)(R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was stirred at room temperature. A mixture of 1,4-dioxadiazole-2-carboxamide (220 mg, 0.43 mmol), oxetane-3-one (157 mg, 2.15 mmol), NaBH 3 CN (135 mg, 2.15 mmol) and ZnCl 2 (585 mg, 4.30 mmol) in 10 mL of MeOH was stirred for 16 h. The mixture was diluted with EtOAc (150 mL) and washed with water (50 mL×2). The organic phase was dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH=15:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid -5-yl)-1,3,4-oxadiazole-2-carboxamide (146 mg, yield: 60%). ESI-MS (M+H) + : 572.3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.42 (d, J = 5.2Hz, 1H), 8.05-7.97 (m, 3H), 7.67 (s, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.22 (d, J = 8.4Hz, 1H), 5.59-5.57 (m, 1H), 4.87-4.6 6(m,4H),4.53-4.50(m,1H),3.98-3.81(m,3H),3.09-3.03(m,1H),2.92-2.86(m,1H),2.29-2.20(m,1H),2.07-2.03(m,1H),1.54-1.51(m,15H)

实施例18.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物18)Example 18. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 18)

1.(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

将(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(4.85g,8.98mmol)、4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(1.88g,8.98mmol)、Pd(dppf)Cl2(734mg,0.9mmol)和K2CO3(2.48g,18mmol)于二噁烷/H2O(4:1,20mL)中的混合物除气并在100℃、N2气氛下搅拌2h。浓缩反应混合物之后，将残余物通过硅胶色谱法(EtOAc:PE＝2:1)纯化，以产生呈黄色固体的(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.4g，产率：51％)。ESI-MS(M+H)+:588.3。(R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine A mixture of tert-butyl-2-carboxylate (4.85 g, 8.98 mmol), 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (1.88 g, 8.98 mmol), Pd(dppf)Cl 2 (734 mg, 0.9 mmol) and K 2 CO 3 (2.48 g, 18 mmol) in dioxane/H 2 O (4:1, 20 mL) was degassed and stirred at 100 °C under N 2 atmosphere for 2 h. After the reaction mixture was concentrated, the residue was purified by silica gel chromatography (EtOAc:PE=2:1) to give (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (3.4 g, yield: 51%). ESI-MS (M+H) + : 588.3.

2.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺的合成2. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,3,4-oxadiazole-2-carboxamide

向(R)-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.4g,5.79mmol)于DCM(10mL)中的溶液中添加TFA(4mL)。在室温下将所得溶液搅拌2h。浓缩反应混合物之后，将残余物溶解于MeOH(10mL)中并用氨水调整至pH＝8。然后添加水(20mL)并用DCM/MeOH溶液(20:1,30mL×3)萃取混合物。将有机相干燥并浓缩，以得到呈黄色固体的粗(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(2.47g，产率：88％)，其用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:488.2。To (R)-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (3.4g, 5.79mmol) was added to a solution of DCM (10mL) with TFA (4mL). The resulting solution was stirred at room temperature for 2h. After the reaction mixture was concentrated, the residue was dissolved in MeOH (10mL) and adjusted to pH=8 with ammonia. Water (20mL) was then added and the mixture was extracted with DCM/MeOH solution (20:1, 30mL×3). The organic phase was dried and concentrated to give a crude (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (2.47 g, yield: 88%), which was used in the next step without further purification. ESI-MS (M+H) + : 488.2.

3.(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成3. (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 1,3,4-oxadiazole-2-carboxamide

向(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(1.5g,3.1mmol)和DIPEA(800mg,6.2mmol)于CH3CN(30mL)中的溶液中添加三氟甲烷磺酸2,2,2-三氟乙酯(1.1g,4.7mmol)。在50℃下将混合物搅拌12h。用水(100mL)稀释之后，用DCM(100mL×3)萃取混合物。将合并的有机层用盐水(100mL)洗涤，干燥(Na2SO4)，过滤并浓缩。将粗产物通过硅胶色谱法(DCM:MeOH＝10:1)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(1.2g，产率：68％)。ESI-MS(M+H)+:570.2。1H NMR(400MHz,CD3OD)δ:8.31(d,J＝5.2Hz,1H),7.94-7.88(m,3H),7.51(s,1H),7.38(d,J＝8.0Hz,1H),7.12(d,J＝5.2Hz,1H),5.49-5.47(m,1H),4.27-4.23(m,1H),4.04-4.00(m,1H),3.78(s,3H),3.33-3.24(m,2H),3.04-2.98(m,2H),2.14-2.05(m,1H),1.87-1.84(m,1H),1.40(s,9H)。To (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 2-(4-(4-(4-nitro-5-yl)-1,3,4-oxadiazole-2-carboxamide (1.5 g, 3.1 mmol) and DIPEA (800 mg, 6.2 mmol) in CH 3 CN (30 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.1 g, 4.7 mmol). The mixture was stirred at 50° C. for 12 h. After dilution with water (100 mL), the mixture was extracted with DCM (100 mL×3). The combined organic layers were washed with brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid -5-yl)-1,3,4-oxadiazole-2-carboxamide (1.2 g, yield: 68%). ESI-MS (M+H) + : 570.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.31 (d, J = 5.2Hz, 1H), 7.94-7.88 (m, 3H), 7.51 (s, 1H), 7.38 (d, J = 8.0Hz, 1H), 7.12 (d, J = 5.2Hz, 1H), 5.49-5.47 (m, 1H), 4.27-4 .23(m,1H),4.04-4.00(m,1H),3.78(s,3H),3.33-3.24(m,2H),3.04-2.98(m,2H),2.14-2.05(m,1H),1.87-1.84(m,1H),1.40(s,9H).

实施例19. 5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物19)Example 19. 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 19)

5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成类似于实施例3中5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(2-(2-羟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(165mg，产率：84％)。ESI-MS(M+H)+:532.2。1H NMR(400MHz,CD3OD)δ:8.42(d,J＝5.2Hz,1H),8.03-8.00(m,3H),7.64(s,1H),7.48(d,J＝8.0Hz,1H),7.23-7.22(m,1H),5.58(d,J＝9.6Hz,1H),4.21-4.09(m,2H),3.90(s,3H),3.74(t,J＝5.6Hz,2H),3.20-3.18(m,2H),2.70-2.62(m,2H),2.30-2.28(m,1H),2.00-1.98(m,1H),1.52(s,9H)。5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in Example 3 was similar. The crude product was purified by preparative HPLC ( CH3CN / H2O with 0.05% NH4HCO3 as mobile phase) to afford 5-(tert-butyl)-N-(2-(2-hydroxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[ c ]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (165 mg, yield: 84%). ESI-MS (M+H) + : 532.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.42 (d, J = 5.2Hz, 1H), 8.03-8.00 (m, 3H), 7.64 (s, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.23-7.22 (m, 1H), 5.58 (d, J = 9.6Hz, 1H), 4.21-4. 09(m,2H),3.90(s,3H),3.74(t,J=5.6Hz,2H),3.20-3.18(m,2H),2.70-2.62(m,2H),2.30-2.28(m,1H),2.00-1.98(m,1H),1.52(s,9H).

实施例20. 5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物20)Example 20. 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 20)

1.(S)-三氟甲烷磺酸四氢呋喃-3-基酯的合成1. Synthesis of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate

在-10℃下向(S)-四氢呋喃-3-醇(500mg,5.7mmol)和吡啶(538mg,6.8mmol)于DCM(15mL)中的溶液中添加Tf2O(1.8g,6.3mmol)。在-10℃下将混合物搅拌0.5h。用2N HCl溶液淬灭混合物。将有机层分离，经Na2SO4干燥并过滤。将所得(S)-三氟甲烷磺酸四氢呋喃-3-基酯的DCM溶液用于下一步骤。ESI-MS(M+H)+:221.0。To a solution of (S)-tetrahydrofuran-3-ol (500 mg, 5.7 mmol) and pyridine (538 mg, 6.8 mmol) in DCM (15 mL) was added Tf 2 O (1.8 g, 6.3 mmol) at -10°C. The mixture was stirred for 0.5 h at -10°C. The mixture was quenched with 2N HCl solution. The organic layer was separated, dried over Na 2 SO 4 and filtered. The resulting DCM solution of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate was used for the next step. ESI-MS (M+H) + : 221.0.

2. 5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺的合成2. 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-methyl)-1,3,4-oxadiazole-2-carboxamide

在-78℃下向(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(1.7g,3.5mmol)于THF(24mL)和DMF(3mL)中的溶液中逐滴添加KHMDS(5.2mL，5.2mmol，1M溶液)。在氮气、-78℃下将溶液搅拌0.5h。然后，逐滴添加(S)-三氟甲烷磺酸四氢呋喃-3-基酯(来自前一步骤)。在室温下将混合物搅拌16h。用水(40mL)稀释之后，用DCM(40mL×3)萃取混合物。将合并的有机层用盐水(60mL)洗涤，干燥(Na2SO4)，过滤并浓缩。将粗产物通过硅胶色谱法(DCM:MeOH＝10:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(448mg，产率：23％)。ESI-MS(M+H)+:558.3。1H NMR(400MHz,DMSO-d6)δ:9.82-9.80(m,1H),9.51(s,1H),8.47(d,J＝4.8Hz,1H),7.99-7.95(m,3H),7.55(s,1H),7.40(d,J＝8.0Hz,1H),7.28(d,J＝5.2Hz,1H),5.43-5.38(m,1H),4.06-3.99(m,2H),3.83-380(m,5H),3.63-3.50(m,2H),3.10-3.05(m,3H),2.22-2.02(m,2H),1.85-1.82(m,2H),1.42(s,9H)。To (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine at -78°C To a solution of (5-yl)-1,3,4-oxadiazole-2-carboxamide (1.7 g, 3.5 mmol) in THF (24 mL) and DMF (3 mL) was added KHMDS (5.2 mL, 5.2 mmol, 1 M solution) dropwise. The solution was stirred for 0.5 h under nitrogen at -78 °C. Then, (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate (from the previous step) was added dropwise. The mixture was stirred at room temperature for 16 h. After dilution with water (40 mL), the mixture was extracted with DCM (40 mL×3). The combined organic layers were washed with brine (60 mL), dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (448 mg, yield: 23%). ESI-MS (M+H) + : 558.3. 1 H NMR (400MHz, DMSO-d 6 ) δ: 9.82-9.80 (m, 1H), 9.51 (s, 1H), 8.47 (d, J = 4.8Hz, 1H), 7.99-7.95 (m, 3H), 7.55 (s, 1H), 7.40 (d, J = 8.0Hz, 1H), 7.28 (d, J = 5.2Hz ,1H),5.43-5.38(m,1H),4.06-3.99(m,2H),3.83-380(m,5H),3.63-3.50(m,2H),3.10-3.05(m,3H),2.22-2.02(m,2H),1.85-1.82(m,2H),1.42(s,9 H).

实施例21. 5-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物21)Example 21. 5-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 21)

向(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(101mg,0.21mmol)于MeOH(7mL)中的溶液中添加(S)-2-甲基环氧乙烷(29μL,0.42mmol)和碳酸铯(135mg,0.42mmol)。在60℃下将混合物搅拌16h。将反应混合物冷却至室温并过滤。将滤液浓缩，并且将粗产物通过硅胶色谱法(DCM:MeOH＝10:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(50mg，产率：44％)。ESI-MS(M+H)+:546.0。1HNMR(400MHz,甲醇-d4)δ:8.41(d,J＝5.3Hz,1H),8.07-8.02(m,2H),7.97(s,1H),7.63(s,1H),7.48(d,J＝8.5Hz,1H),7.22(d,J＝5.3Hz,1H),5.62-5.53(m,1H),4.33-4.10(m,2H),4.04-3.95(m,1H),3.89(s,3H),3.33-3.27(m,2H),2.58-2.46(m,2H),2.38-2.23(m,1H),2.07-1.95(m,1H),1.48(s,9H),1.15(d,J＝6.3Hz,3H)。To (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of (5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide (101 mg, 0.21 mmol) in MeOH (7 mL) was added (S)-2-methyloxirane (29 μL, 0.42 mmol) and cesium carbonate (135 mg, 0.42 mmol). The mixture was stirred at 60 ° C for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography (DCM: MeOH = 10: 1) to give 5-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (50 mg, yield: 44%). ESI-MS (M+H) + : 546.0. 1 HNMR (400 MHz, methanol-d 4 )δ:8.41(d,J＝5.3Hz,1H),8.07-8.02(m,2H),7.97(s,1H),7.63(s,1H),7.48(d,J＝8.5Hz,1H),7.22(d,J＝5.3Hz,1H),5.62-5.53(m,1H),4.33-4.10(m ,2H),4.04-3.95(m,1H),3.89(s,3H),3.33-3.27(m,2H),2.58-2.46(m,2H),2.38-2.23(m,1H),2.07-1.95(m,1H),1.48(s,9H),1.15(d,J＝6.3Hz, 3H).

实施例22. 5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物22)Example 22. 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 22)

1.(R)-三氟甲烷磺酸四氢呋喃-3-基酯的合成1. Synthesis of (R)-tetrahydrofuran-3-yl trifluoromethanesulfonate

(R)-三氟甲烷磺酸四氢呋喃-3-基酯的合成类似于实施例20步骤1中(S)-三氟甲烷磺酸四氢呋喃-3-基酯的合成。将所得DCM溶液用于下一步骤。ESI-MS(M+H)+:221.0。The synthesis of (R)-tetrahydrofuran-3-yl trifluoromethanesulfonate was similar to that of (S)-tetrahydrofuran-3-yl trifluoromethanesulfonate in step 1 of Example 20. The resulting DCM solution was used in the next step. ESI-MS (M+H) + : 221.0.

2. 5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1,3,4-噁二唑-2-甲酰胺(I-RP58)的合成2. 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-amino-1,3,4-oxadiazole-2-carboxamide (I-RP58)

5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成类似于实施例20步骤2中5-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成。将粗产物通过硅胶色谱法(DCM:MeOH＝10:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-((S)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(50mg，产率：38％)。ESI-MS(M+H)+:558.1。1H NMR(400MHz,甲醇-d4)δ:8.38(d,J＝5.3Hz,1H),8.03-7.95(m,3H),7.60(s,1H),7.45(d,J＝8.5Hz,1H),7.19(d,J＝5.3Hz,1H),5.56(br d,J＝9.3Hz,1H),4.12-4.01(m,2H),4.01-3.90(m,2H),3.88(s,3H),3.79-3.68(m,2H),3.29-3.21(m,1H),3.20-3.09(m,1H),2.33-2.11(m,2H),2.09-1.90(m,2H),1.48(s,9H)。5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in step 2 of Example 20 was similar. The crude product was purified by silica gel chromatography (DCM:MeOH=10:1) to give 5-(tert-butyl)-N-((S)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (50 mg, yield: 38%). ESI-MS (M+H) + : 558.1. 1 H NMR (400MHz, methanol- d 4 ) δ: 8.38 (d, J = 5.3Hz, 1H), 8.03-7.95 (m, 3H), 7.60 (s, 1H), 7.45 (d, J = 8.5Hz, 1H), 7.19 (d, J = 5.3Hz, 1H), 5.56 (br d, J = 9.3Hz, 1H), 4. 12-4.01(m,2H),4.01-3.90(m,2H),3.88(s,3H),3.79-3.68(m,2H),3.29 -3.21(m,1H),3.20-3.09(m,1H),2.33-2.11(m,2H),2.09-1.90(m,2H),1. 48(s,9H).

实施例23. 1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物23)Example 23. 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 23)

1. 8-溴-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的制备1. 8-Bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Preparation of tert-butyl 2-carboxylate

向8-溴-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(556mg,3.06mmol)于CH2Cl2(10mL)中的溶液中添加HATU(1.16g,3.06mmol)和DIPEA(592mg,4.6mmol)。在室温下将混合物搅拌1h，之后添加1-(叔丁基)-1H-1,2,3-三唑-4-羧酸(1.04g,3.06mmol)。在室温下将混合物搅拌12h。将混合物用CH2Cl2(200mL)稀释，用水(100mL)、盐水(100mL)洗涤，干燥并浓缩。将粗产物通过硅胶柱(PE:EtOAc＝1:1)纯化，以得到呈黄色固体的8-溴-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(1.1g，产率：73％)。ESI-MS(M+H)+:492.1。1H NMR(400MHz,CDCl3)δ:8.17(s,1H),7.35-7.33(m,2H),7.21(d,J＝8.0Hz,1H),5.52-5.42(m,1H),4.54-4.34(m,2H),4.04-3.86(m,1H),3.65-3.55(m,1H),2.80(s,9H),2.10-2.07(m,2H),1.41(s,9H)。8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine To a solution of tert-butyl-2-carboxylate (556 mg, 3.06 mmol) in CH 2 Cl 2 (10 mL) was added HATU (1.16 g, 3.06 mmol) and DIPEA (592 mg, 4.6 mmol). The mixture was stirred at room temperature for 1 h, after which 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (1.04 g, 3.06 mmol) was added. The mixture was stirred at room temperature for 12 h. The mixture was diluted with CH 2 Cl 2 (200 mL), washed with water (100 mL), brine (100 mL), dried and concentrated. The crude product was purified by silica gel column (PE: EtOAc = 1: 1) to give 8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (1.1 g, yield: 73%). ESI-MS (M+H) + : 492.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.17 (s, 1H), 7.35-7.33 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 5.52-5.42 (m, 1H), 4.54-4.34 (m, 2H), 4.04-3.86 (m, 1H), 3.65-3.55 (m, 1H), 2.80 (s, 9H), 2.10-2.07 (m, 2H), 1.41 (s, 9H).

2. 5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的制备2. 5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Preparation of tert-butyl 2-carboxylate

5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于实施例7中5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成。将粗产物通过硅胶柱色谱法(CH2Cl2:MeOH＝20:1)纯化，以得到呈黄色固体的5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(170mg，Y:35％)。ESI-MS(M+H)+:601.2。5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that of 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine in Example 7. The crude product was purified by silica gel column chromatography (CH 2 Cl 2 :MeOH=20:1) to give 5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (170 mg, Y: 35%). ESI-MS (M+H) + : 601.2.

3. 1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的制备3. 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于实施例7中5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物(135mg，产率：95％)用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:501.2。1-(tert-Butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that in Example 7. Synthesis of 2-(5-yl)-1,2,4-oxadiazole-3-carboxamide. The crude product (135 mg, yield: 95%) was used in the next step without further purification. ESI-MS (M+H) + : 501.2.

4. 1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的制备4. 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Preparation of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于实施例7中5-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物通过硅胶柱色谱法(EtOAc:MeOH＝10:1)纯化，以得到呈黄色固体的1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(67mg，产率：45％)。ESI-MS(M+H)+:556.7。1H NMR(400MHz,DMSO-d6)δ:9.48(s,1H),9.02(d,J＝8.8Hz,1H),8.76(s,1H),8.46(d,J＝5.2Hz,1H),7.97-7.91(m,3H),7.56(s,1H),7.37(d,J＝8.0Hz,1H),7.25(d,J＝5.2Hz,1H),5.47-5.43(m,1H),4.61-1.47(m,4H),4.13-4.08(m,2H),3.88-3.65(m,3H),2.90-2.78(m,2H),2.15-2.06(m,1H),1.88-1.82(m,1H),1.65(s,9H),1.36(t,J＝7.2Hz,3H)。1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 5-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that in Example 7. The crude product was purified by silica gel column chromatography (EtOAc:MeOH=10:1) to give 1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (67 mg, yield: 45%). ESI-MS (M+H) + : 556.7. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.48 (s, 1H), 9.02 (d, J=8.8 Hz, 1H), 8.76 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 7.97-7.91 (m, 3H), 7.56 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.25 (d, J=5.2 Hz, 1H), 5.47-5. 43(m,1H),4.61-1.47(m,4H),4.13-4.08(m,2H),3.88-3.65(m,3H),2.90-2.78(m,2H),2.15-2.06(m,1H),1.88-1.82(m,1H),1.65(s,9H),1.36(t ,J=7.2Hz,3H).

实施例24.(R)-1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物24a)和(S)-1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物24b)Example 24. (R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 24a) and (S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 24b)

使1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(50mg)经历SFC分离(2.1×25.0cm(S,S)Whelk0-1，具有0.5％异丙基胺/CO2的58％甲醇，120巴，85mL/min，230nm，甲醇)并产生23mg峰1(化学纯度99％，ee>99％)和24mg峰2(化学纯度99％，ee＝99％)。1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (50 mg) was subjected to SFC separation (2.1×25.0 cm (S,S) Whelk 0-1, 58% methanol with 0.5% isopropylamine/CO 2 , 120 bar, 85 mL/min, 230 nm, methanol) and produced 23 mg of peak 1 (chemical purity 99%, ee>99%) and 24 mg of peak 2 (chemical purity 99%, ee=99%).

峰1被指定为(R)-1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺：LCMS:Rt 4.0min，m/z 557.20。1H NMR(400MHz,甲醇-d4)δppm8.51(s,1H),8.40(d,J＝5.27Hz,1H),8.05-7.92(m,3H),7.64(s,1H),7.47(d,J＝8.28Hz,1H),7.21(d,J＝5.27Hz,1H),5.57(br d,J＝9.04Hz,1H),4.78-4.71(m,1H),4.71-4.65(m,3H),4.17(q,J＝7.28Hz,2H),4.01-3.91(m,1H),3.91-3.78(m,2H),3.15-2.98(m,1H),2.88(ddd,J＝12.99Hz,9.60Hz,3.51Hz,1H),2.36-2.14(m,1H),2.11-1.87(m,1H),1.73(s,9H),1.46(t,J＝7.28Hz,3H)。Peak 1 was assigned to (R)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide: LCMS: Rt 4.0 min, m/z 557.20. 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 8.51 (s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.05-7.92 (m, 3H), 7.64 (s, 1H), 7.47 (d, J=8.28 Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 5.57 (br d,J＝9.04Hz,1H),4.78-4.71(m,1H),4.71-4.65(m,3H),4.17(q,J＝7.28Hz,2H),4.01-3.91(m,1H),3.91-3.78(m,2H),3.15-2.98(m,1H),2.88(ddd, J＝12.99Hz,9.60Hz,3.51Hz,1H),2.36-2.14(m,1H),2.11-1.87(m,1H),1.73(s,9H),1.46(t,J＝7.28Hz,3H).

峰2被指定为(S)-1-(叔丁基)-N-(8-(2-((1-乙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺：LCMS:Rt 5.3min，m/z 557.00。1H NMR(400MHz,甲醇-d4)δppm 8.51(s,1H),8.40(d,J＝5.27Hz,1H),8.06-7.92(m,3H),7.64(s,1H),7.47(d,J＝8.03Hz,1H),7.21(d,J＝5.27Hz,1H),5.57(br d,J＝9.29Hz,1H),4.77-4.70(m,1H),4.70-4.63(m,2H),4.17(q,J＝7.28Hz,2H),4.05-3.91(m,1H),3.91-3.76(m,2H),3.15-2.98(m,1H),2.89(ddd,J＝12.8Hz,9.7Hz,3.6Hz,1H),2.40-2.13(m,1H),2.12-1.87(m,1H),1.74(s,9H),1.47(t,J＝7.28Hz,3H)。Peak 2 was assigned to (S)-1-(tert-butyl)-N-(8-(2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide: LCMS: Rt 5.3 min, m/z 557.00. 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 8.51 (s, 1H), 8.40 (d, J=5.27 Hz, 1H), 8.06-7.92 (m, 3H), 7.64 (s, 1H), 7.47 (d, J=8.03 Hz, 1H), 7.21 (d, J=5.27 Hz, 1H), 5.57 (br d,J＝9.29Hz,1H),4.77-4.70(m,1H),4.70-4.63(m,2H),4.17(q,J＝7.28Hz,2H),4.05-3.91(m,1H),3.91-3.76(m,2H),3.15-2.98(m,1H),2.89(ddd, J＝12.8Hz,9.7Hz,3.6Hz,1H),2.40-2.13(m,1H),2.12-1.87(m,1H),1.74(s,9H),1.47(t,J＝7.28Hz,3H).

实施例25.(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物25)Example 25. (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 25)

1.(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成(实施例9步骤3)。将粗物质通过硅胶色谱法(EtOAc:PE＝4:1)纯化，以得到呈黄色固体的(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(520mg，产率：56％)。ESI-MS(M+H)+:615.3。(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that of (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (Example 9, step 3). The crude material was purified by silica gel chromatography (EtOAc:PE=4:1) to give (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (520 mg, yield: 56%). ESI-MS (M+H) + : 615.3.

2.(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的合成2. (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于实施例9步骤4中(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物分离为黄色固体并用于下一步骤而无需进一步纯化(420mg，产率：96％)。ESI-MS(M+H)+:515.3。(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in step 4 of Example 9 was similar. Synthesis of 2-(5-yl)-1,2,4-oxadiazole-3-carboxamide. The crude product was isolated as a yellow solid and used in the next step without further purification (420 mg, yield: 96%). ESI-MS (M+H) + : 515.3.

3.(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺(I-RP35)的合成3. (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-amino-1H-1,2,3-triazole-4-carboxamide (I-RP35)

(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于实施例17中(R)-5-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺的合成。将粗物质通过硅胶色谱法(DCM:MeOH＝20:1)纯化，以得到呈黄色固体的(R)-1-(叔丁基)-N-(8-(2-((1-异丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(116mg，产率：51％)。ESI-MS(M+H)+:571.2。1H NMR(400MHz,CDCl3)δ:8.42(d,J＝4.8Hz,1H),8.17(s,1H),8.07(d,J＝8.8Hz,1H),7.94(s,1H),7.85(d,J＝8.0Hz,1H),7.77(s,1H),7.57(s,1H),7.48(d,J＝8.0Hz,1H),7.11(s,1H),7.03(d,J＝5.2Hz,1H),5.64(t,J＝8.0Hz,1H),4.78-4.68(m,4H),4.53-4.45(m,1H),3.91-3.80(m,3H),3.04-2.99(m,1H),2.82-2.79(m,1H),2.27-2.23(m,1H),2.10-2.05(m,1H),1.70(s,9H),1.55(s,3H),1.52(s,3H)。(R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine in Example 17 was similar to that of (R)-5-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The crude material was purified by silica gel chromatography (DCM:MeOH=20:1) to afford (R)-1-(tert-butyl)-N-(8-(2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (116 mg, yield: 51%). ESI-MS (M+H) + : 571.2. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.42 (d, J=4.8 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 7.03 (d, J=5.2 Hz, 1H), 5.64 ( t,J＝8.0Hz,1H),4.78-4.68(m,4H),4.53-4.45(m,1H),3.91-3.80(m,3H),3.04-2.99(m,1H),2.82-2.79(m,1H),2.27-2.23(m,1H),2.10-2.05(m, 1H),1.70(s,9H),1.55(s,3H),1.52(s,3H).

实施例26. 1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物26a)和1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物26b)Example 26. 1-(tert-Butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 26a) and 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 26b)

1.(R)-8-溴-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成1. (R)-8-Bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

(R)-8-溴-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于实施例12步骤1中8-溴-5-(5-(叔丁基)-1,3,4-噁二唑-2-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯的合成。将粗产物通过硅胶柱色谱法(EtOAc/石油醚＝1:2)纯化，以得到呈黄色固体的(R)-8-溴-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(2.3g，产率：95％)。ESI-MS(M+H)+:492.2。(R)-8-Bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that of 8-bromo-5-(5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamido)-4,5-dihydro-1H-benzo[c]azepine in step 1 of Example 12. -Synthesis of tert-butyl 2(3H)-carboxylate. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether=1:2) to give (R)-8-bromo-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid -2-carboxylic acid tert-butyl ester (2.3 g, yield: 95%). ESI-MS (M+H) + : 492.2.

2.(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成2. (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成类似于实施例9步骤1中所述的(R)-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成。将粗产物用于下一步骤而无需纯化。ESI-MS(M+H)+:540.3。(R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine The synthesis of tert-butyl-2-carboxylate was similar to that described in Example 9, Step 1: (R)-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -Synthesis of tert-butyl 2-carboxylate. The crude product was used in the next step without purification. ESI-MS (M+H) + : 540.3.

3.(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成3. (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

向(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(5.4g,10.0mmol)于二噁烷/H2O(100mL)中的溶液中添加4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(2.1g,10.0mmol)，添加K2CO3(2.8g,20.0mmol)和Pd(dppf)Cl2(0.4g,0.5mmol)。在100℃、氮气下将混合物搅拌16h。冷却至室温之后，将混合物浓缩并通过硅胶柱色谱法(石油醚/EtOAc＝1:3)纯化，以得到呈黄色固体的(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.2g，产率：55％)。ESI-MS(M+H)+:586.7。1H NMR(400MHz,CDCl3)δ:8.42(s,1H),8.19(s,1H),8.02-7.87(m,3H),7.68(s,1H),7.54-7.49(m,2H),7.06(d,J＝5.2Hz,1H),5.63-5.58(m,1H),4.83-4.67(m,1H),4.51-4.47(m,1H),4.02-4.00(m,1H),3.93(s,3H),3.65-3.62(m,1H),2.14-2.12(m,2H),1.72(s,9H),1.41-1.38(m,9H)。To (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine To a solution of tert-butyl-2-carboxylate (5.4 g, 10.0 mmol) in dioxane/H 2 O (100 mL) was added 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (2.1 g, 10.0 mmol), K 2 CO 3 (2.8 g, 20.0 mmol) and Pd(dppf)Cl 2 (0.4 g, 0.5 mmol) The mixture was stirred at 100° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was concentrated and purified by silica gel column chromatography (petroleum ether/EtOAc=1:3) to give (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (3.2 g, yield: 55%). ESI-MS (M+H) + : 586.7. 1 H NMR (400MHz, CDCl 3 ) δ: 8.42 (s, 1H), 8.19 (s, 1H), 8.02-7.87 (m, 3H), 7.68 (s, 1H), 7.54-7.49 (m, 2H), 7.06 (d, J = 5.2Hz, 1H), 5.63-5.58 (m, 1H), 4.83-4 .67(m,1H),4.51-4.47(m,1H),4.02-4.00(m,1H),3.93(s,3H),3.65-3.62(m,1H),2.14-2.12(m,2H),1.72(s,9H),1.41-1.38(m,9H).

4.(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的合成4. (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

向(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.2g,5.5mmol)于DCM(30mL)中的溶液中添加TFA(30mL)。在室温下将混合物搅拌3h。移除溶剂。将粗物质溶解于MeOH(30mL)/水(20mL)中。将混合物用NH4OH碱化至pH＝8-9并用DCM(3×50mL)萃取。将合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩，以得到呈灰色固体的(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(2.6g，产率：98％)。ESI-MS(M+H)+:486.7。To (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (3.2g, 5.5mmol) in DCM (30mL) was added TFA (30mL). The mixture was stirred at room temperature for 3h. The solvent was removed. The crude material was dissolved in MeOH (30mL)/water (20mL). The mixture was basified to pH=8-9 with NH 4 OH and extracted with DCM (3×50mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a gray solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (2.6 g, yield: 98%). ESI-MS (M+H) + : 486.7.

5. 1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺和1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的合成5. 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine 5-yl)-1H-1,2,3-triazole-4-carboxamide and 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

向(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(500mg,1.0mmol)于MeOH(30mL)中的溶液中添加二氢呋喃-3(2H)-酮(258mg,3.0mmol)、ZnCl2(682mg,5.0mmol)和NaBH3CN(189mg,3.0mmol)。在50℃下将混合物搅拌16h。将混合物浓缩并通过硅胶柱色谱法(DCM/MeOH＝20/1至15/1)纯化，以得到呈黄色固体的外消旋产物(542mg，产率：79％)。To (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1H-5-yl)-1H-1,2,3-triazole-4-carboxamide (500 mg, 1.0 mmol) in MeOH (30 mL) was added dihydrofuran-3(2H)-one (258 mg, 3.0 mmol), ZnCl 2 (682 mg, 5.0 mmol) and NaBH 3 CN (189 mg, 3.0 mmol). The mixture was stirred at 50° C. for 16 h. The mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH=20/1 to 15/1) to give the racemic product (542 mg, yield: 79%) as a yellow solid.

将1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((S)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(154mg)和1-(叔丁基)-N-((R)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-((R)-四氢呋喃-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(167mg)通过手性拆分分离。ESI-MS(M+H)+:557.3。1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((S)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (154 mg) and 1-(tert-butyl)-N-((R)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-((R)-tetrahydrofuran-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (167 mg) was separated by chiral resolution. ESI-MS (M+H) + : 557.3.

异构物1：1H NMR(400MHz,CD3OD)δ:8.53(s,1H),8.42(d,J＝5.2Hz,1H),8.05-7.99(m,3H),7.64(s,1H),7.48(d,J＝8.4Hz,1H),7.23(d,J＝5.2Hz,1H),5.58(d,J＝10.4Hz,1H),4.16-4.09(m,2H),4.02-3.96(m,2H),3.90(s,3H),3.79-3.71(m,2H),3.31-3.24(m,2H),3.15-3.10(m,1H),2.31-2.17(m,2H),2.07-1.97(m,2H),1.74(s,9H)。Isomer 1: 1 H NMR (400 MHz, CD 3 OD)δ:8.53(s,1H),8.42(d,J＝5.2Hz,1H),8.05-7.99(m,3H),7.64(s,1H),7.48(d,J＝8.4Hz,1H),7.23(d,J＝5.2Hz,1H),5.58(d,J＝10.4Hz,1H),4.16-4 .09(m,2H),4.02-3.96(m,2H),3.90(s,3H),3.79-3.71(m,2H),3.31-3.24(m,2H),3.15-3.10(m,1H),2.31-2.17(m,2H),2.07-1.97(m,2H),1.74 (s,9H).

异构物2：1H NMR(400MHz,CD3OD)δ:8.43(s,1H),8.30(d,J＝5.2Hz,1H),7.95-7.86(m,3H),7.67(s,1H),7.37(d,J＝8.0Hz,1H),7.13(d,J＝5.2Hz,1H),5.47(d,J＝9.6Hz,1H),4.00(br,2H),3.93-3.85(m,2H),3.85(s,3H),3.69-3.58(m,2H),3.28-3.22(m,1H),3.17-2.97(m,2H),2.21-2.01(m,2H),1.99-1.80(m,2H),1.63(s,9H)。Isomer 2: 1 H NMR (400 MHz, CD 3 OD)δ:8.43(s,1H),8.30(d,J＝5.2Hz,1H),7.95-7.86(m,3H),7.67(s,1H),7.37(d,J＝8.0Hz,1H),7.13(d,J＝5.2Hz,1H),5.47(d,J＝9.6Hz,1H),4.00(br, 2H),3.93-3.85(m,2H),3.85(s,3H),3.69-3.58(m,2H),3.28-3.22(m,1H),3.17-2.97(m,2H),2.21-2.01(m,2H),1.99-1.80(m,2H),1.63(s,9H).

实施例27a.(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物27)Example 27a. (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 27)

向(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(500mg,1.0mmol)于MeOH(30mL)中的溶液中添加氧杂环丁烷-3-酮(216mg,3.0mmol)、ZnCl2(682mg,5.0mmol)和NaBH3CN(189mg,3.0mmol)。在50℃下将混合物搅拌3h。将混合物浓缩并将粗物质通过硅胶色谱法(CH2Cl2:MeOH自20:1分级至15:1)纯化，以得到呈黄色固体的(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(307mg，产率：55％)。ESI-MS(M+H)+:542.7。1H NMR(400MHz,CD3OD)δ:8.54(s,1H),8.42(d,J＝5.6Hz,1H),8.04-7.98(m,3H),7.71(s,1H),7.49(d,J＝8.0Hz,1H),7.24(d,J＝5.2Hz,1H),5.59(d,J＝9.2Hz,1H),4.79-4.75(m,1H),4.71-4.69(m,3H),4.00-3.83(m,6H),3.09-3.05(m,1H),3.94-2.88(m,1H),2.29-2.21(m,1H),2.07-2.04(m,1H),1.75(s,9H)。To (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (4-nitro-5-yl) -1H -1,2,3-triazole-4-carboxamide (500 mg, 1.0 mmol) in MeOH (30 mL) was added oxetan-3-one (216 mg, 3.0 mmol), ZnCl 2 (682 mg, 5.0 mmol) and NaBH 3 CN (189 mg, 3.0 mmol). The mixture was stirred at 50° C. for 3 h. The mixture was concentrated and the crude material was purified by silica gel chromatography (CH 2 Cl 2 :MeOH graded from 20:1 to 15:1) to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (307 mg, yield: 55%). ESI-MS (M+H) + : 542.7. 1 H NMR (400MHz, CD 3 OD) δ: 8.54 (s, 1H), 8.42 (d, J = 5.6Hz, 1H), 8.04-7.98 (m, 3H), 7.71 (s, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.24 (d, J = 5.2Hz, 1H), 5.59 (d, J = 9.2 Hz,1H),4.79-4.75(m,1H),4.71-4.69(m,3H),4.00-3.83(m,6H),3.09-3.05(m,1H),3.94-2.88(m,1H),2.29-2.21(m,1H),2.07-2.04(m,1H),1.75 (s,9H).

实施例27b.(R)-1-(叔丁基)-N-(8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺Example 27b. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide

1. 1-(甲基-d3)-1H-吡唑-4-胺的合成1. Synthesis of 1-(methyl-d3)-1H-pyrazole-4-amine

在35℃下将4-硝基-1-吡唑(5.0g,44mmol)和硫酸d6-二甲酯(10.0g,75.7mmol)于1M NaOH水溶液(50.0mL)中的混合物加热过夜。将形成的固体过滤，用水洗涤并干燥(Na2SO4)，以得到呈白色晶体的l-d3-甲基-4-硝基-1-吡唑(3.9g，产率：68％)。LCMS:室温0.36min；MH+131.1；1H NMR(400MHz,DMSO-d6)δ:8.84(s,1H),8.23(s,1H)。A mixture of 4-nitro-1-pyrazole (5.0 g, 44 mmol) and d6-dimethyl sulfate (10.0 g, 75.7 mmol) in 1 M aqueous NaOH solution (50.0 mL ) was heated overnight at 35°C. The solid formed was filtered, washed with water and dried ( Na2SO4 ) to give 1-d3-methyl-4-nitro-1-pyrazole (3.9 g, yield: 68%) as white crystals. LCMS: RT 0.36 min; MH+ 131.1; 1H NMR (400 MHz, DMSO-d6) δ: 8.84 (s, 1H), 8.23 (s, 1H).

2. 1-(甲基-d3)-4-硝基-1H-吡唑的合成2. Synthesis of 1-(methyl-d3)-4-nitro-1H-pyrazole

将1-d3-甲基-4-硝基-1-吡唑(3.9g,30mmol)于EtOH(50.0mL)中的溶液用氮气除气，接着添加10％钯/碳(0.32g,0.30mmol)。将混合物放置于氢气气氛下并在室温下搅拌2h。将混合物过滤，并且将滤液在真空中浓缩，以得到呈油状物的1-(d3-甲基-1H-吡唑-4-胺(2.9g，产率：96％)，其用于下一步骤而无需进一步纯化。A solution of 1-d3-methyl-4-nitro-1-pyrazole (3.9 g, 30 mmol) in EtOH (50.0 mL) was degassed with nitrogen, followed by the addition of 10% palladium on carbon (0.32 g, 0.30 mmol). The mixture was placed under a hydrogen atmosphere and stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 1-(d3-methyl-1H-pyrazole-4-amine (2.9 g, yield: 96%) as an oil, which was used in the next step without further purification.

3. 4-甲氧基-N-(1-(甲基-d3)-1H-吡唑-4-基)嘧啶-2-胺的合成3. Synthesis of 4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine

向2-氯-4-甲氧基嘧啶(9.4g,65.1mmol)于1,4-二噁烷(0.3L)中的溶液中添加1-甲基-d3-1H-吡唑-4-胺(8.5g,85mmol)、Cs2CO3(63.6g,195mmol)、S-Phos(13.3g,0.03mol)和Pd2(dba)3(16.7g,0.02mol)。在回流、N2下将反应混合物搅拌16h。将反应混合物冷却至室温，并且将混合物通过硅胶垫过滤并用EtOAc(500mL)洗涤。将合并的滤液在真空中浓缩。将粗物质通过硅胶色谱法(庚烷:EtOAc＝100:0至0:100)纯化，以得到呈淡黄色固体的4-甲氧基-N-(1-(甲基-d3)-1H-吡唑-4-基)嘧啶-2-胺(9.2g，产率：68％)。ESI-MS(M+H)+:209.1。1HNMR(400MHz,CDCl3)δ:8.10(d,J＝5.7Hz,1H),7.77(s,1H),7.51(s,1H),6.13(d,J＝5.7Hz,1H),3.94(s,3H)。To a solution of 2-chloro-4-methoxypyrimidine (9.4 g, 65.1 mmol) in 1,4-dioxane (0.3 L) was added 1-methyl-d3-1H-pyrazole-4-amine (8.5 g, 85 mmol), Cs2CO3 ( 63.6 g, 195 mmol), S-Phos (13.3 g, 0.03 mol) and Pd2 (dba) 3 (16.7 g, 0.02 mol). The reaction mixture was stirred at reflux, N2 for 16 h. The reaction mixture was cooled to room temperature, and the mixture was filtered through a pad of silica gel and washed with EtOAc (500 mL). The combined filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (heptane: EtOAc = 100:0 to 0: 100) to give 4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (9.2 g, yield: 68%) as a light yellow solid. ESI-MS (M+H) + : 209.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.10 (d, J = 5.7 Hz, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 6.13 (d, J = 5.7 Hz, 1H), 3.94 (s, 3H).

4. 4-氯-N-(1-(甲基-d3)-1H-吡唑-4-基)嘧啶-2-胺的合成4. Synthesis of 4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine

向4-甲氧基-N-(1-(甲基-d3)-1H-吡唑-4-基)嘧啶-2-胺(9.1g,43.7mmol)中添加HBr(90mL,38％水溶液)。将反应混合物加热至100℃，并且在所述温度下搅拌3h。将反应混合物冷却至室温并在真空中浓缩，用甲苯(3×100mL)恒沸并在50℃下干燥过夜，以得到呈黄色/棕色固体的HBr盐(16g)。然后将盐溶解于POCl3(250mL)并加热至100℃持续36h。将反应混合物冷却至室温并在真空中浓缩，并且用甲苯(3×100mL)恒沸。用EtOAc(500mL)稀释所得残余物并将水(100mL)和层分离。用EtOAc(3×100mL)萃取水层，并且将合并的有机层用盐水(200mL)洗涤，干燥(Na2SO4)，过滤并在真空中浓缩，以得到残余物，将残余物与EtOAc/庚烷(1:1)一起研磨，以得到呈白色固体的4-氯-N-(1-(甲基-d3)-1H-吡唑-4-基)嘧啶-2-胺(7.4g，产率：80％)。ESI-MS(M+H)+:213.0。To 4-methoxy-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (9.1 g, 43.7 mmol) was added HBr (90 mL, 38% aqueous solution). The reaction mixture was heated to 100°C and stirred at that temperature for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, azeotroped with toluene (3×100 mL) and dried at 50°C overnight to give the HBr salt (16 g) as a yellow/brown solid. The salt was then dissolved in POCl 3 (250 mL) and heated to 100°C for 36 h. The reaction mixture was cooled to room temperature and concentrated in vacuo, and azeotroped with toluene (3×100 mL). The resulting residue was diluted with EtOAc (500 mL) and the water (100 mL) and layers were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with brine (200 mL ), dried ( Na2SO4 ), filtered and concentrated in vacuo to give a residue that was triturated with EtOAc/heptane (1:1) to give 4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (7.4 g, yield: 80%) as a white solid. ESI-MS (M+H) + : 213.0.

5.(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂2-羧酸叔丁酯的合成5. (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine Synthesis of tert-butyl 2-carboxylate

向(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(4.6g,8.5mmol)于1,4-二噁烷(100mL)和水(20mL)中的溶液中添加4-氯-N-(1-(甲基-d3)-1H-吡唑-4-基)嘧啶-2-胺(1.8g,8.5mmol)，添加K2CO3(2.4g,17mmol)和Pd(dppf)Cl2(0.7g,0.85mmol)。在100℃、氮气下将混合物搅拌16h。冷却至室温之后，将混合物用EtOAc(300mL)稀释并用饱和盐水(100mL)洗涤。用EtOAc(3×100mL)萃取水层，并且将有机物合并，干燥(Na2SO4)，过滤，在真空中浓缩以得到残余物。将粗物质通过硅胶柱色谱法(梯度庚烷/EtOAc＝100:0-0:100)纯化，以得到呈黄色固体的(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.2g，产率：55％)ESI-MS(M+H)+:590.4。To (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine To a solution of tert-butyl-2-carboxylate (4.6 g, 8.5 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added 4-chloro-N-(1-(methyl-d3)-1H-pyrazol-4-yl)pyrimidin-2-amine (1.8 g, 8.5 mmol), K 2 CO 3 (2.4 g, 17 mmol) and Pd(dppf)Cl 2 (0.7 g, 0.85 mmol). The mixture was stirred at 100° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (300 mL) and washed with saturated brine (100 mL). The aqueous layer was extracted with EtOAc (3×100 mL), and the organics were combined, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo to give a residue. The crude material was purified by silica gel column chromatography (gradient heptane/EtOAc = 100:0-0:100) to afford (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine as a yellow solid. -2-carboxylic acid tert-butyl ester (3.2 g, yield: 55%) ESI-MS (M+H) + : 590.4.

6.(R)-1-(叔丁基)-N-(8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的合成6. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

向(R)-5-(1-(叔丁基)-1H-1,2,3-三唑-4-甲酰氨基)-8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯(3.2g,5.5mmol)于CH2Cl2(40mL)中的溶液中添加TFA(40mL)。在室温下将混合物搅拌3h。将溶剂移除并将粗物质再溶解于MeOH(30mL)/水(20mL)中。将混合物用NH4OH碱化至pH＝8-9并用CH2Cl2(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤，经Na2SO4干燥，过滤并在真空中浓缩，以得到呈黄色固体的(R)-1-(叔丁基)-N-(8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(3.0g，产率：86％)。ESI-MS(M+H)+:490.2。To (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine -2-carboxylic acid tert-butyl ester (3.2g, 5.5mmol) in CH 2 Cl 2 (40mL) was added TFA (40mL). The mixture was stirred at room temperature for 3h. The solvent was removed and the crude material was redissolved in MeOH (30mL)/water (20mL). The mixture was basified to pH=8-9 with NH 4 OH and extracted with CH 2 Cl 2 (3×100mL). The combined organic layers were washed with brine (100mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo to give (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (3.0 g, yield: 86%). ESI-MS (M+H) + : 490.2.

7.(R)-1-(叔丁基)-N-(8-(2-((1-(甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺。7. (R)-1-(tert-butyl)-N-(8-(2-((1-(methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetane-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide.

将(R)-1-(叔丁基)-N-(8-(2-((1-甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(2.6g,15.9mmol)溶解于MeOH(160mL)中并用氧杂环丁烷-3-酮(1.15g,16.0mmol)、ZnCl2(3.6g,26.5mmol)和NaBH3CN(1.0mg,15.9mmol)处理。在50℃下将混合物搅拌16h，在真空中浓缩，并且将粗物质通过硅胶色谱法(梯度CH2Cl2:MeOH 100:10)纯化，以得到黄色固体，将其通过溶解于MeOH(100mL)和CH2Cl2(500mL)中进一步洗涤纯化，并且用水(100mL)和饱和盐水(100mL)洗涤，将有机层分离，干燥(Na2SO4)，过滤并在真空中浓缩，以得到呈黄色固体的(R)-1-(叔丁基)-N-(8-(2-((1-甲基-d3)-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(2.32g，67％产率：55％)。ESI-MS(M+H)+:546.3。1H NMR(400MHz,DMSO-d6)δ:9.46(s,1H),8.98(d,J＝8.3Hz,1H),8.74(s,1H),8.46(d,J＝5.6Hz,1H),7.95(m,3H),7.54(s,1H),7.38(d,J＝8.1Hz,1H),7.25(d,J＝5.2Hz,1H),5.45(m,1H),4.61-4.47(m,4H),3.86(m,1H),3.78(m,1H),3.67(m,1H),2.93(m,1H),2.77(m,1H),2.12(m,1H),1.86(m,1H),1.66(s,9H)。(R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (2.6 g, 15.9 mmol) was dissolved in MeOH (160 mL) and treated with oxetan-3-one (1.15 g, 16.0 mmol), ZnCl 2 (3.6 g, 26.5 mmol) and NaBH 3 CN (1.0 mg, 15.9 mmol). The mixture was stirred at 50 °C for 16 h, concentrated in vacuo, and the crude material was purified by silica gel chromatography ( gradient CH2Cl2 :MeOH 100:10) to give a yellow solid, which was further purified by dissolving in MeOH (100 mL) and CH2Cl2 (500 mL ) and washed with water (100 mL) and saturated brine (100 mL), the organic layer was separated, dried ( Na2SO4 ) , filtered and concentrated in vacuo to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-d3)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (2.32 g, 67% Yield: 55%). ESI-MS (M+H) + : 546.3. 1 H NMR (400MHz, DMSO-d 6 ) δ: 9.46 (s, 1H), 8.98 (d, J = 8.3Hz, 1H), 8.74 (s, 1H), 8.46 (d, J = 5.6Hz, 1H), 7.95 (m, 3H), 7.54 (s, 1H), 7.38 (d, J = 8.1Hz, 1H), 7.25 ( d,J＝5.2Hz,1H),5.45(m,1H),4.61-4.47(m,4H),3.86(m,1H),3.78(m,1H),3.67(m,1H),2.93(m,1H),2.77(m,1H),2.12(m,1H),1.86(m,1H),1.66(s ,9H).

实施例27c.化合物27的晶形A和晶形G的制备Example 27c. Preparation of Form A and Form G of Compound 27

在室温(25℃)下将化合物(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(1200g,2.47mol)添加至20L反应器中，接着在25℃下添加24L 1,2-二氯乙烷。向溶液中添加氧杂环丁烷-3-酮(534g,24.7mol)、NaBH(OAc)3(523g,2.47mol)和AcOH(24mL,0.17当量)。在室温下将额外量NaBH(OAc)3(1046g,4.94mol)一次性添加至反应器中。在25℃下将混合物搅拌16h。在室温下将冰水(12kg)缓慢添加至反应器中。将有机层分离，并且用二氯甲烷(3×12L)萃取水层三次。将合并的有机层用盐水(20L)洗涤，经Na2SO4干燥，过滤并浓缩。将粗物质通过硅胶色谱法(CH2Cl2:MeOH＝20:1)纯化，以得到(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(氧杂环丁烷-3-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物27)。Compound (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was added at room temperature (25°C). -5-yl)-1H-1,2,3-triazole-4-carboxamide (1200 g, 2.47 mol) was added to a 20 L reactor, followed by 24 L of 1,2-dichloroethane at 25 °C. To the solution was added oxetane-3-one (534 g, 24.7 mol), NaBH(OAc) 3 (523 g, 2.47 mol) and AcOH (24 mL, 0.17 eq.). An additional amount of NaBH(OAc) 3 (1046 g, 4.94 mol) was added to the reactor in one portion at room temperature. The mixture was stirred at 25 °C for 16 h. Ice water (12 kg) was slowly added to the reactor at room temperature. The organic layer was separated, and the aqueous layer was extracted three times with dichloromethane (3×12 L). The combined organic layers were washed with brine (20 L), dried over Na 2 SO 4 , filtered and concentrated. The crude material was purified by silica gel chromatography ( CH2Cl2 : MeOH = 20: 1) to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 27).

将纯化的化合物27(950g)和EtOH(5L)剧烈搅拌4h，并且将浆料过滤并用1L EtOH洗涤。在45℃下将所得湿滤饼在真空下干燥约24h，直至达到恒重以得到晶形A(960g，产率85.7％，纯度99％)。Purified compound 27 (950 g) and EtOH (5 L) were vigorously stirred for 4 h, and the slurry was filtered and washed with 1 L EtOH. The wet cake was dried under vacuum at 45 ° C for about 24 h until constant weight was reached to obtain Form A (960 g, yield 85.7%, purity 99%).

将300.2mg晶形A称重至20mL玻璃小瓶中，接着添加6mL乙酸异丙酯(IPAc)以供悬浮。在50℃下以约1000rpm的速率将样品磁力搅拌三天。三天后将固体通过过滤来分离，然后在室温、真空下干燥约5h，以产生晶形G。300.2 mg of Form A was weighed into a 20 mL glass vial, followed by the addition of 6 mL of isopropyl acetate (IPAc) for suspension. The sample was magnetically stirred at a rate of about 1000 rpm at 50° C. for three days. After three days, the solid was isolated by filtration and then dried at room temperature under vacuum for about 5 h to produce Form G.

或者，向2.1g晶形A中装填15体积二氯甲烷(mL/g)。在Tj-Tr＝20K且Tj最大＝110℃的条件下使用迪安-斯塔克分离器(Dean-Stark trap)在气氛条件下蒸馏所得混合物，其中Tj＝护套温度，Tr＝反应/反应器温度，并且Tj最大＝最大护套温度。移除5mL或2体积二氯甲烷，接着添加2体积乙酸异丙酯(IPAc)。在Tj-Tr＝40K且Tj最大＝110℃的条件下继续蒸馏直至移除10mL或5体积溶剂。然后添加5体积IPAc，接着继续蒸馏以再移除10mL或5体积溶剂。添加5体积IPAc，接着添加30mL IPAc。搅拌所得混合物，并且在周末使温度在20℃至60℃之间循环以形成浆料，并且将形式G从浆料分离。Alternatively, 15 volumes of dichloromethane (mL/g) were charged to 2.1 g of Form A. The resulting mixture was distilled under atmospheric conditions using a Dean-Stark trap at Tj -Tr = 20K and Tjmax = 110°C, where Tj = jacket temperature, Tr = reaction/reactor temperature, and Tjmax = maximum jacket temperature. 5 mL or 2 volumes of dichloromethane were removed, followed by the addition of 2 volumes of isopropyl acetate (IPAc). Distillation was continued at Tj - Tr = 40K and Tjmax = 110°C until 10 mL or 5 volumes of solvent were removed. 5 volumes of IPAc were then added, followed by continued distillation to remove another 10 mL or 5 volumes of solvent. 5 volumes of IPAc were added, followed by the addition of 30 mL of IPAc. The resulting mixture was stirred, and the temperature was cycled between 20°C and 60°C over the weekend to form a slurry, and Form G was separated from the slurry.

粉末X射线衍射Powder X-ray diffraction

使用利用Cu Ka辐射的XRD-D8 X射线粉末衍射计(Bruker,Madison,WI)研究化合物的结晶性。仪器配备有长细焦X射线管。管电压和安培数分别设定至40kV和40mA。发散和散射狭缝设定成1°，并且接收狭缝设定成0.15mm。衍射辐射通过Lynxeye检测器检测。使用在1.6°/min下从3至42°2θ的θ-2θ连续扫描。通过将其放置于零背景板上来制备样品以供分析。The crystallinity of the compounds was studied using an XRD-D8 X-ray powder diffractometer (Bruker, Madison, WI) using Cu Ka radiation. The instrument was equipped with a long fine focus X-ray tube. The tube voltage and amperage were set to 40 kV and 40 mA, respectively. The divergence and scattering slits were set to 1 °, and the receiving slit was set to 0.15 mm. The diffracted radiation was detected by a Lynxeye detector. A θ-2θ continuous scan from 3 to 42 ° 2θ at 1.6 °/min was used. The samples were prepared for analysis by placing them on a zero background plate.

晶形A的粉末X射线衍射(PXRD)图示出于图1中，并且主峰列举于表1中。晶形G的PXRD图示出于图4中，并且主峰列举于表2中。The powder X-ray diffraction (PXRD) pattern of Form A is shown in FIG1 , and the main peaks are listed in Table 1. The PXRD pattern of Form G is shown in FIG4 , and the main peaks are listed in Table 2.

表1.晶形A的PXRD峰清单Table 1. PXRD peak list of Form A

表2.晶形G的PXRD峰清单Table 2. PXRD peak list of Form G

2θ角2θ angle 净强度Net Strength 相对强度Relative Strength 3.623.62 1071.51071.5 0.580.58 8.928.92 96.896.8 0.050.05 10.9610.96 184.5184.5 0.100.10 12.5912.59 206.5206.5 0.110.11 14.5314.53 81.681.6 0.040.04 15.4115.41 252.1252.1 0.140.14 16.3316.33 133.3133.3 0.070.07 18.4418.44 294.9294.9 0.160.16 20.1820.18 701.1701.1 0.380.38 21.7921.79 1860.21860.2 1.001.00 23.3623.36 205.8205.8 0.110.11 25.4025.40 502.9502.9 0.270.27 26.7826.78 34.534.5 0.020.02 34.1834.18 28.828.8 0.020.02

差示扫描量热法(DSC)和热重分析(TGA)Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA)

使用Discovery差示扫描量热仪(DSC)(TA Instruments)和Discovery热重量分析仪(TGA)(TA Instruments)检查化合物的热性质。将样品密封于密闭铝DSC托盘中以供DSC分析并于敞开的铝托盘中以供TGA分析。DSC和TGA研究均以10℃/分钟的从25℃至300℃的线性梯度执行热分析。The thermal properties of the compounds were examined using a Discovery differential scanning calorimeter (DSC) (TA Instruments) and a Discovery thermogravimetric analyzer (TGA) (TA Instruments). The samples were sealed in closed aluminum DSC trays for DSC analysis and in open aluminum trays for TGA analysis. Both DSC and TGA studies performed thermal analysis with a linear gradient from 25°C to 300°C at 10°C/min.

晶形A的差示扫描量热法(DSC)分析显示形式A的起始温度为175.6℃并且熔融温度为186℃(图2)。Differential Scanning Calorimetry (DSC) analysis of Form A showed that Form A had an onset temperature of 175.6°C and a melting temperature of 186°C (Figure 2).

晶形G的DSC分析显示形式G的起始温度为215.4℃并且熔融温度为217.3℃(图5)。DSC analysis of Form G showed that Form G had an onset temperature of 215.4°C and a melting temperature of 217.3°C (Figure 5).

化合物27的形式A的TGA分析显示3.16％失重，这指示形式A为水合物(图3)。TGA analysis of Form A of Compound 27 showed a 3.16% weight loss, indicating that Form A was a hydrate ( FIG. 3 ).

化合物27的形式G的TGA分析显示直至熔融也没有失重，这指示形式G为无水的(图5)。TGA analysis of Form G of Compound 27 showed no weight loss until melting, indicating that Form G is anhydrous ( FIG. 5 ).

固态NMRSolid-state NMR

在Champaign,IL的Spectral Data Services的363MHz Tecmag Redstone分光计上获得13C CP/MAS(交叉极化/魔角旋转)固态NMR谱。将每种样品装填至以kel-F端帽封闭的7mm(OD)氧化锆转子中以供随后进行数据采集。所有三份样品在转子中均为约一半满。在Doty XC 7mm CP/MAS探针上以91MHz的观测频率获得13C CP/MAS NMR谱(旋转7kHz，1H脉宽5.0μs，谱宽29.8kHz，采集时间0.0344s，CP脉宽2ms，松弛延迟5.0s，扫描数1296)。谱参考在176ppm下的甘氨酸羰基碳的外部样品的化学位移并使用Nuts处理(谱线增宽为10Hz)。使用MNOVA处理谱的峰列表和重迭。 13 C CP/MAS (cross polarization/magic angle spinning) solid-state NMR spectra were obtained on a 363 MHz Tecmag Redstone spectrometer from Spectral Data Services in Champaign, IL. Each sample was loaded into a 7 mm (OD) zirconia rotor closed with a kel-F end cap for subsequent data acquisition. All three samples were approximately half full in the rotor. 13 C CP/MAS NMR spectra were obtained on a Doty XC 7 mm CP/MAS probe at an observation frequency of 91 MHz (spin 7 kHz, 1H pulse width 5.0 μs, spectrum width 29.8 kHz, acquisition time 0.0344 s, CP pulse width 2 ms, relaxation delay 5.0 s, scan number 1296). The spectra were referenced to the chemical shift of an external sample of the carbonyl carbon of glycine at 176 ppm and processed using Nuts (line broadening of 10 Hz). Peak lists and overlaps of the spectra were processed using MNOVA.

形式A和形式G的13C CP/MAS固态NMR分别示出于图3B和图6B中。诊断性化学位移列举于表3中。 13 C CP/MAS solid state NMR of Form A and Form G are shown in Figure 3B and Figure 6B, respectively. The diagnostic chemical shifts are listed in Table 3.

表3.化合物27的固体形式的诊断性13C CP/MAS NMR化学位移Table 3. Diagnostic 13 C CP/MAS NMR Chemical Shifts of Solid Form of Compound 27

*此为基于化学结构和ChemDraw化学位移预测以及DMSO中溶液13C NMR谱的临时指定*This is a provisional designation based on the chemical structure and ChemDraw chemical shift predictions and the 13 C NMR spectrum of the solution in DMSO

实施例28.(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物28)Example 28. (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 28)

向(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(200mg,0.4mmol)于CH3CN(5mL)中的溶液中添加三氟甲烷磺酸2,2,2-三氟乙酯(190mg,0.6mmol)。在50℃下将混合物搅拌12h。浓缩反应混合物之后，将残余物通过硅胶色谱法(PE:EtOAc＝1:1)纯化，以得到呈黄色固体的(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(85mg，产率：36％)。ESI-MS(M+H)+:569.3。1H NMR(400MHz,CD3OD)δ:8.54(s,1H),8.42(d,J＝5.2Hz,1H),8.03-7.99(m,3H),7.61(s,1H),7.49(d,J＝7.6Hz,1H),7.22(d,J＝5.2Hz,1H),5.60-5.57(m,1H),4.39-4.35(m,1H),4.17-4.12(m,1H),3.89(s,3H)3.43-3.32(m,2H),3.16-3.09(m,2H),2.24-2.20(m,1H),1.98-1.94(m,1H),1.74(s,9H)。To (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin- 4 -yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (5 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (190 mg, 0.6 mmol). The mixture was stirred at 50° C. for 12 h. After the reaction mixture was concentrated, the residue was purified by silica gel chromatography (PE:EtOAc=1:1) to give (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (85 mg, yield: 36%). ESI-MS (M+H) + : 569.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.54 (s, 1H), 8.42 (d, J = 5.2Hz, 1H), 8.03-7.99 (m, 3H), 7.61 (s, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.22 (d, J = 5.2Hz, 1H), 5.60-5.57 (m, 1H),4.39-4.35(m,1H),4.17-4.12(m,1H),3.89(s,3H)3.43-3.32(m,2H),3.16-3.09(m,2H),2.24-2.20(m,1H),1.98-1.94(m,1H),1.74(s,9H).

实施例29. 1-(叔丁基)-N-((R)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物29)Example 29. 1-(tert-Butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 29)

向(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(250mg,0.51mmol)于EtOH(5mL)中的溶液中添加(R)-2-甲基环氧乙烷(58mg,1.0mmol)。在50℃下将混合物搅拌24h。浓缩之后，将残余物通过硅胶柱(石油醚/EtOAc＝1:2)纯化，以得到呈白色固体的1-(叔丁基)-N-((R)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(110mg，产率：40％)。ESI-MS(M+H)+:545.3。1H NMR(400MHz,CD3OD)δ:8.42(s,1H),8.28(d,J＝5.2Hz,1H),7.93-7.84(m,3H),7.52(s,1H),7.35(d,J＝8.8Hz,1H),7.09(d,J＝5.2Hz,1H),5.46(d,J＝10Hz,1H),4.13-4.00(m,2H),3.92-3.87(m,1H),3.78(s,3H)3.21-3.12(m,2H),2.40-2.32(m,2H),2.17-2.13(m,1H),1.89-1.84(m,1H),1.62(s,9H),1.02(d,J＝6.0Hz,3H)。To (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of (R)-2-methyloxirane (58 mg, 1.0 mmol) in EtOH (5 mL) was added (R)-2-methyloxirane (58 mg, 1.0 mmol). The mixture was stirred at 50 °C for 24 h. After concentration, the residue was purified by silica gel column (petroleum ether/EtOAc=1:2) to give 1-(tert-butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a white solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (110 mg, yield: 40%). ESI-MS (M+H) + : 545.3. 1 H NMR (400 MHz, CD 3 OD)δ:8.42(s,1H),8.28(d,J＝5.2Hz,1H),7.93-7.84(m,3H),7.52(s,1H),7.35(d,J＝8.8Hz,1H),7.09(d,J＝5.2Hz,1H),5.46(d,J＝10Hz,1H),4.13-4.0 0(m,2H),3.92-3.87(m,1H),3.78(s,3H)3.21-3.12(m,2H),2.40-2.32(m,2H),2.17-2.13(m,1H),1.89-1.84(m,1H),1.62(s,9H),1.02(d,J＝6.0Hz, 3H).

实施例30. 1-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物30)Example 30. 1-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 30)

1-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于1-(叔丁基)-N-((R)-2-((R)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成(实施例29)。将粗物质通过制备型TLC(DCM/MeOH＝10:1)纯化，以得到呈黄色固体的1-(叔丁基)-N-((R)-2-((S)-2-羟丙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(97mg，产率：44％)。ESI-MS(M+H)+:545.3。1H NMR(400MHz,CD3OD)δ:8.54(s,1H),8.41(d,J＝5.2Hz,1H),8.01-7.97(m,3H),7.63(s,1H),7.46(d,J＝8.0Hz,1H),7.22(d,J＝5.6Hz,1H),5.57(d,J＝9.6Hz,1H),4.23-4.20(m,1H),4.12-4.07(m,1H),4.02-3.97(m,1H),3.90(s,3H),3.30-3.28(m,1H),3.26-3.19(m,1H),2.47-2.45(m,2H),2.31-2.22(m,1H),2.01-1.97(m,1H),1.74(s,9H),1.16(d,J＝6.4Hz,3H)。1-(tert-Butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of 1-(tert-butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that of 1-(tert-butyl)-N-((R)-2-((R)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The crude material was purified by preparative TLC (DCM/MeOH=10:1) to give 1-(tert-butyl)-N-((R)-2-((S)-2-hydroxypropyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1H-1,2,3-triazole-4-carboxamide (97 mg, yield: 44%). ESI-MS (M+H) + : 545.3. 1 H NMR (400 MHz, CD 3 OD) δ: 8.54 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.01-7.97 (m, 3H), 7.63 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 5.6 Hz, 1H), 5.57 (d, J = 9.6 Hz, 1H), 4.23-4.20 (m, 1H), 4.12-4.07 (m,1H),4.02-3.97(m,1H),3.90(s,3H),3.30-3.28(m,1H),3.26-3.19(m,1H),2.47-2.45(m,2H),2.31-2.22(m,1H),2.01-1.97(m,1H),1.74(s,9 H), 1.16 (d, J = 6.4Hz, 3H).

实施例31.(R)-1-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(化合物31)Example 31. (R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 31)

向(R)-1-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(140mg,0.29mmol)于MeOH(10mL)中的溶液中添加1-溴-2-甲氧基乙烷(121mg,0.87mmol)和K2CO3(120mg,0.87mmol)。在80℃下将混合物搅拌16h。用水(20mL)稀释之后，用CH2Cl2(30mL×2)萃取混合物。将合并的有机层用H2O(20mL×2)洗涤，干燥(Na2SO4)，过滤并浓缩。将粗物质通过制备型TLC(DCM:MeOH＝20:1)纯化，以得到呈黄色固体的(R)-1-(叔丁基)-N-(2-(2-甲氧基乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺(66mg，产率：42％)。ESI-MS(M+H)+:545.1。1H NMR(400MHz,CDCl3)δ:8.41(d,J＝5.2Hz,1H),8.18(s,1H),7.98(d,J＝8.4Hz,1H),7.90(s,1H),7.84(d,J＝8.0Hz,1H),7.80(s,1H),7.53(s,1H),7.46(d,J＝8.0Hz,1H),7.04(d,J＝5.2Hz,1H),6.97(s,1H),5.60(t,J＝8.8Hz,1H),4.19-4.07(m,2H),3.91(s,3H),3.57(t,J＝5.6Hz,2H),3.37(s,3H),3.32-3.26(m,1H),3.19-3.15(m,1H),2.78-2.69(m,2H),2.24-2.20(m,1H),2.02-1.99(m,1H),1.70(s,9H)。To (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of 1-bromo-2-methoxyethane (140 mg, 0.29 mmol) in MeOH (10 mL) was added 1-bromo-2-methoxyethane (121 mg, 0.87 mmol) and K 2 CO 3 (120 mg, 0.87 mmol). The mixture was stirred at 80° C. for 16 h. After dilution with water (20 mL), the mixture was extracted with CH 2 Cl 2 (30 mL×2). The combined organic layers were washed with H 2 O (20 mL×2), dried (Na 2 SO 4 ), filtered and concentrated. The crude material was purified by preparative TLC (DCM:MeOH=20:1) to give (R)-1-(tert-butyl)-N-(2-(2-methoxyethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid -5-yl)-1H-1,2,3-triazole-4-carboxamide (66 mg, yield: 42%). ESI-MS (M+H) + : 545.1. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.41 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H), 5.60 (t, J＝8.8Hz,1H),4.19-4.07(m,2H),3.91(s,3H),3.57(t,J＝5.6Hz,2H),3.37(s,3H),3.32-3.26(m,1H),3.19-3.15(m,1H),2.78-2.69(m,2H),2.24-2. 20(m,1H),2.02-1.99(m,1H),1.70(s,9H).

实施例32.(R)-5-(叔丁基)-N-(2-(2,2-二氟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物32)Example 32. (R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine -5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 32)

向(R)-5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(105mg,0.21mmol)于CH3CN(8mL)中的溶液中添加1,1-二氟-2-碘乙烷(23μL,0.26mmol)和碳酸钾(89mg,0.64mmol)。在80℃下将混合物搅拌18h。将反应混合物冷却至室温并过滤。将滤液浓缩并将粗产物通过制备型HPLC(具有0.05％TFA的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(2-(2,2-二氟乙基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,3,4-噁二唑-2-甲酰胺(30mg，产率：25％)。ESI-MS(M+H)+:552.0。1H NMR(400MHz,甲醇-d4)δ:8.42(d,J＝5.3Hz,1H),8.23(d,J＝8.4Hz,1H),8.19(s,1H),7.95(s,1H),7.68-7.65(m,1H),7.62(d,J＝7.8Hz,1H),7.30(d,J＝5.5Hz,1H),6.40(tt,J＝53.5Hz,3.6Hz,1H),5.70(dd,J＝9.8Hz,2.5Hz,1H),4.83(br d,J＝14.3Hz,1H),4.67(br d,J＝14.3Hz,1H),3.90(s,3H),3.83-3.67(m,2H),3.59(dt,J＝15.0Hz,3.4Hz,2H),2.52-2.31(m,2H),1.49(s,9H)To (R)-5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine To a solution of (R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-(( 1 -methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro- 1H -benzo[c]azepine (R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-(( 1- methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was added (R)-5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a yellow solid. -5-yl)-1,3,4-oxadiazole-2-carboxamide (30 mg, yield: 25%). ESI-MS (M+H) + : 552.0. 1 H NMR (400 MHz, methanol- d 4 ) δ: 8.42 (d, J = 5.3 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 7.68-7.65 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 5.5 Hz, 1H), 6.40 (tt, J = 53.5 Hz, 3.6 Hz, 1H), 5.70 (dd, J = 9.8 Hz, 2.5 Hz, 1H), 4.83 (br d, J = 14.3 Hz, 1H), 4.67 (br d,J＝14.3Hz,1H),3.90(s,3H),3.83-3.67(m,2H),3.59(dt,J＝15.0Hz,3.4Hz,2H),2.52-2.31(m,2H),1.49(s,9H)

实施例33. 5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物33)Example 33. 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 33)

1.(E)-5-(3-溴苯基)戊-4-烯酸1. (E)-5-(3-bromophenyl)pent-4-enoic acid

在0℃下向溴化(3-羧基丙基)三苯基鏻(12.87g,30mmol,1.0当量)于无水DMSO(50mL)的溶液中分批添加NaH(3g,75mmol,2.5当量)。在室温下将反应物搅拌30min，之后逐滴添加3-溴苯甲醛(5.5g,30mmol,1.0当量)。在室温下将混合物再搅拌2h，然后倾倒至水(200mL)中并用EtOAc(100mL)萃取。将水溶液用浓HCl酸化并用EtOAc(200mL×3)萃取。将合并的有机层用盐水(100mL×3)洗涤。将有机层经硫酸钠干燥并在减压下浓缩。将残余物通过硅胶柱(石油醚/EtOAc＝2:1)纯化，以得到呈黄色油状物的(E)-5-(3-溴苯基)戊-4-烯酸(4.4g，产率：58％)。ESI-MS(M+1)+:254.9。1H NMR(400MHz,CDCl3)δ:7.48(s,1H),7.33(d,J＝7.6Hz,1H),7.23(d,J＝8.0Hz,1H),7.15(t,J＝8.0Hz,1H),6.39-6.35(m,1H),6.23-6.19(m,1H),2.55-2.53(m,4H)。To a solution of (3-carboxypropyl)triphenylphosphonium bromide (12.87 g, 30 mmol, 1.0 equiv) in anhydrous DMSO (50 mL) was added NaH (3 g, 75 mmol, 2.5 equiv) in portions at 0°C. The reaction was stirred at room temperature for 30 min, after which 3-bromobenzaldehyde (5.5 g, 30 mmol, 1.0 equiv) was added dropwise. The mixture was stirred for another 2 h at room temperature, then poured into water (200 mL) and extracted with EtOAc (100 mL). The aqueous solution was acidified with concentrated HCl and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (100 mL×3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether/EtOAc=2:1) to give (E)-5-(3-bromophenyl)pent-4-enoic acid (4.4 g, yield: 58%) as a yellow oil. ESI-MS (M+1) + : 254.9. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.48 (s, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.39-6.35 (m, 1H), 6.23-6.19 (m, 1H), 2.55-2.53 (m, 4H).

2. 5-(3-溴苯基)戊烯酸的合成2. Synthesis of 5-(3-bromophenyl)pentenoic acid

向(E)-5-(3-溴苯基)戊-4-烯酸(2.4g,9.4mmol,1.0当量)于乙醇(20mL)中的溶液中添加PtO2(200mg,10％)。在氢气气氛下将混合物搅拌1h。将催化剂过滤出，并且将所得滤液浓缩以得到呈黄色固体的目的化合物5-(3-溴苯基)戊烯酸(2.1g，产率：87％)，将其用于下一步骤而无需进一步纯化。ESI-MS(M+1)+:256.9。1H NMR(400MHz,CD3OD)δ:7.24(s,1H),7.21-7.18(m,1H),7.06-7.03(m,2H),2.50(t,J＝6.8Hz,2H),2.20(t,J＝6.8Hz,2H),1.53-1.51(m,4H)。To a solution of (E)-5-(3-bromophenyl)pent-4-enoic acid (2.4 g, 9.4 mmol, 1.0 equiv) in ethanol (20 mL) was added PtO 2 (200 mg, 10%). The mixture was stirred for 1 h under a hydrogen atmosphere. The catalyst was filtered off, and the resulting filtrate was concentrated to give the target compound 5-(3-bromophenyl)pentenoic acid (2.1 g, yield: 87%) as a yellow solid, which was used in the next step without further purification. ESI-MS (M+1) + : 256.9. 1 H NMR (400MHz, CD 3 OD) δ: 7.24 (s, 1H), 7.21-7.18 (m, 1H), 7.06-7.03 (m, 2H), 2.50 (t, J = 6.8 Hz, 2H), 2.20 (t, J = 6.8 Hz, 2H), 1.53-1.51 (m, 4H).

3. 2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-酮的合成3. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one

在130℃下将5-(3-溴苯基)戊烯酸(2.1g,8.2mmol,1.0当量)于PPA(5ml)中的混合物搅拌1h。冷却之后，用NaOH(1N)将混合物碱化至pH＝7～8。用EtOAc(200mL×2)萃取混合物。将合并的有机层浓缩并通过制备型HPLC(梯度:5％B增加至95％B，A：0.5％NH3水溶液，B：CH3CN)纯化，以得到呈无色油状物的2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-酮(1.1g，产率：56％)。ESI-MS(M+H)+:239.0。1H NMR(400MHz,CDCl3)δ:7.59(d,J＝8.4Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),7.38(s,1H),2.89(t,J＝6.8Hz,2H),2.72(t,J＝6.0Hz,2H),1.90-1.79(m,4H)。A mixture of 5-(3-bromophenyl)pentenoic acid (2.1 g, 8.2 mmol, 1.0 equiv) in PPA (5 ml) was stirred at 130 ° C for 1 h. After cooling, the mixture was basified to pH = 7-8 with NaOH (1 N). The mixture was extracted with EtOAc (200 mL × 2). The combined organic layers were concentrated and purified by preparative HPLC (gradient: 5% B increased to 95% B, A: 0.5% NH 3 aqueous solution, B: CH 3 CN) to give 2-bromo-6,7,8,9-tetrahydro-5H-benzo [7] annulene-5-one (1.1 g, yield: 56%) as a colorless oil. ESI-MS (M + H) + : 239.0. 1 H NMR (400MHz, CDCl 3 ) δ: 7.59 (d, J = 8.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (s, 1H), 2.89 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H), 1.90-1.79 (m, 4H).

4. 2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-醇的合成4. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-ol

向2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-酮(600mg,2.5mmol,1.0当量)于MeOH(10mL)中的溶液中添加NaBH4(144mg,3.8mmol,1.5当量)，并且然后在室温下搅拌1h。蒸发溶剂之后，将残余物通过硅胶柱(EtOAc/己烷＝1:5)纯化，以得到呈白色固体的2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-醇(600mg，产率：99％)。ESI-MS(M+H-17)+:222.9。1H NMR(400MHz,CDCl3)δ:7.34-7.30(m,2H),7.24(s,1H),4.88-4.86(m,1H),2.88-8.82(m,1H),2.70-2.63(m,1H),2.08-2.00(m,2H),1.81-1.72(m,4H)。To a solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (600 mg, 2.5 mmol, 1.0 equiv) in MeOH (10 mL) was added NaBH 4 (144 mg, 3.8 mmol, 1.5 equiv) and then stirred at room temperature for 1 h. After evaporation of the solvent, the residue was purified by silica gel column (EtOAc/hexane=1:5) to give 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-ol (600 mg, yield: 99%) as a white solid. ESI-MS (M+H-17) + : 222.9. 1 H NMR (400MHz, CDCl 3 )δ:7.34-7.30(m,2H),7.24(s,1H),4.88-4.86(m,1H),2.88-8.82(m,1H),2.70-2.63(m,1H),2.08-2.00(m,2H),1.81-1.72(m,4H ).

5. 5-叠氮基-2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯的合成5. Synthesis of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene

将2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-醇(600mg,2.5mmol,1.0当量)于甲苯(10mL)中的溶液在冰浴中在N2下冷却并一次性用DPPA(2.06g,7.5mmol,3.0当量)处理，接着用DBU(1.14g,7.5mmol,3.0当量)处理。将反应温度保持0℃持续1h，然后升温至室温持续12h。将混合物用EtOAc(100mL)稀释，用2N HCl(2×50mL)、盐水洗涤，并且将有机层经Na2SO4干燥，过滤然后浓缩。将粗产物通过硅胶柱(用PE洗脱)纯化，以得到呈黄色油状物的5-叠氮基-2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯(350mg，产率：45％)。ESI-MS(M+H-N3)+:223.0。1HNMR(400MHz,CDCl3)δ:7.31-7.29(m,2H),7.15(d,J＝8.0Hz,1H),4.72(t,J＝5.2Hz,1H),2.99-2.92(m,1H),2.70-2.64(m,1H),2.08-2.00(m,1H),1.90-1.59(m,5H)。A solution of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-ol (600 mg, 2.5 mmol, 1.0 equiv) in toluene (10 mL) was cooled in an ice bath under N2 and treated with DPPA (2.06 g, 7.5 mmol, 3.0 equiv) in one portion followed by DBU (1.14 g, 7.5 mmol, 3.0 equiv). The reaction temperature was maintained at 0 °C for 1 h and then warmed to room temperature for 12 h. The mixture was diluted with EtOAc (100 mL), washed with 2N HCl (2 x 50 mL), brine, and the organic layer was dried over Na2SO4 , filtered and concentrated. The crude product was purified by silica gel column (eluted with PE) to give 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (350 mg, yield: 45%) as a yellow oil. ESI-MS (M+HN 3 ) + : 223.0. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.31-7.29 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 4.72 (t, J=5.2 Hz, 1H), 2.99-2.92 (m, 1H), 2.70-2.64 (m, 1H), 2.08-2.00 (m, 1H), 1.90-1.59 (m, 5H).

6. 2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-胺的合成6. Synthesis of 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-amine

向5-叠氮基-2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯(375mg,1.4mmol,1.0当量)于THF(5mL)和H2O(0.5mL)中的混合物中添加PPh3(741mg,2.8mmol,2.0当量)。在室温下将混合物搅拌12h。将混合物用HCl(1N)酸化至pH＝1并用EtOAc(100mL)萃取。用NaOH(1N)将分离的水层碱化至pH＝10。将所得沉淀物收集并干燥，以得到呈白色固体的2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-胺(360mg，产率：100％)。ESI-MS(M+H-17)+:222.9。To a mixture of 5-azido-2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (375 mg, 1.4 mmol, 1.0 equiv) in THF (5 mL) and H 2 O (0.5 mL) was added PPh 3 (741 mg, 2.8 mmol, 2.0 equiv). The mixture was stirred at room temperature for 12 h. The mixture was acidified to pH=1 with HCl (1 N) and extracted with EtOAc (100 mL). The separated aqueous layer was basified to pH=10 with NaOH (1 N). The resulting precipitate was collected and dried to give 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-amine (360 mg, yield: 100%) as a white solid. ESI-MS (M+H-17) + : 222.9.

7.(2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯7. Tert-butyl (2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

向(2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(360mg,1.5mmol,1.0当量)于CH2Cl2(5mL)和三乙胺(303mg,3.0mmol,2.0当量)中的溶液中添加Boc2O(394mg,1.8mmol,1.2当量)。在室温下将混合物搅拌2h。用EtOAc(100mL)稀释之后，将混合物用水(100mL×2)洗涤。将有机层浓缩并通过硅胶柱(PE:EtOAc＝30:1)纯化，以得到呈白色固体的(2-溴-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(310mg，产率：61％)。ESI-MS(M-55):284.0。1H NMR(400MHz,CDCl3)δ:7.29-7.23(m,2H),7.10(d,J＝8.0Hz,1H),4.92-4.82(m,2H),2.84-2.75(m,2H),1.88-1.83(m,5H),1.44(s,9H)。To a solution of tert-butyl (2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate (360 mg, 1.5 mmol, 1.0 equiv) in CH 2 Cl 2 (5 mL) and triethylamine (303 mg, 3.0 mmol, 2.0 equiv) was added Boc 2 O (394 mg, 1.8 mmol, 1.2 equiv). The mixture was stirred at room temperature for 2 h. After dilution with EtOAc (100 mL), the mixture was washed with water (100 mL×2). The organic layer was concentrated and purified by silica gel column (PE:EtOAc=30:1) to give tert-butyl (2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate (310 mg, yield: 61%) as a white solid. ESI-MS (M-55): 284.0. 1 H NMR (400MHz, CDCl 3 ) δ: 7.29-7.23 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 4.92-4.82 (m, 2H), 2.84-2.75 (m, 2H), 1.88-1.83 (m, 5H), 1.44 (s, 9H).

8.(2-(2-氯嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成8. Synthesis of tert-butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

(2-(2-氯嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成类似于4-(2-氯嘧啶-4-基)-2-甲基苄基氨基甲酸叔丁酯的合成。将混合物浓缩并通过硅胶柱(PE:EtOAc＝4:1)纯化，以得到呈白色固体的(2-(2-氯嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(200mg，产率：66％)。ESI-MS(M+H)+:374.1。The synthesis of tert-butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate is similar to that of tert-butyl 4-(2-chloropyrimidin-4-yl)-2-methylbenzylcarbamate. The mixture was concentrated and purified by silica gel column (PE:EtOAc=4:1) to give tert-butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate (200 mg, yield: 66%) as a white solid. ESI-MS (M+H) + : 374.1.

9.(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成9. Synthesis of tert-butyl (2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

在100℃、N2下将(2-(2-氯嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(500mg,1.34mmol)、1-甲基-1H-吡唑-4-胺(195mg,2.01mmol)、Pd2(dba)3(120mg,0.13mmol)、S-phos(111mg,0.27mmol)和Cs2CO3(870mg,2.68mmol)于1,4-二噁烷(12ml)中的混合物搅拌6h。将混合物通过硅藻土垫过滤并将滤液浓缩。将残余物通过硅胶柱(EtOAc)纯化，以得到呈白色固体的(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(480mg，产率：83％)。ESI-MS(M+H)+:435.3。1H NMR(400MHz,CDCl3)δ:8.46(d,J＝5.2Hz,1H),7.88-7.80(m,3H),7.38-6.85(m,4H),4.97-4.94(m,2H),3.85(s,3H),2.96-2.94(m,2H),1.93-1.64(m,6H),1.47(s,9H)。A mixture of tert-butyl (2-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (500 mg , 1.34 mmol), 1-methyl-1H-pyrazol-4-amine (195 mg, 2.01 mmol), Pd 2 (dba) 3 (120 mg, 0.13 mmol), S-phos (111 mg, 0.27 mmol) and Cs 2 CO 3 (870 mg, 2.68 mmol) in 1,4-dioxane (12 ml) was stirred at 100° C. under N 2 for 6 h. The mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column (EtOAc) to give tert-butyl (2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (480 mg, yield: 83%) as a white solid. ESI-MS (M+H) + : 435.3. 1 H NMR (400MHz, CDCl 3 ) δ: 8.46 (d, J = 5.2Hz, 1H), 7.88-7.80 (m, 3H), 7.38-6.85 (m, 4H), 4.97-4.94 (m, 2H), 3.85 (s, 3H), 2.96-2.94 (m, 2H), 1.93-1.64 (m, 6H),1.47(s,9H).

10. 4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成10. Synthesis of 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

在室温下将(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(240mg,0.55mmol)于TFA(4.0mL)和CH2Cl2(4.0mL)中的混合物搅拌2h。然后将反应混合物浓缩以得到呈黄色油状物的化合物4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(250mg，粗)，将其用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:335.3。A mixture of tert-butyl (2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate (240 mg, 0.55 mmol) in TFA (4.0 mL) and CH 2 Cl 2 (4.0 mL) was stirred at room temperature for 2 h. The reaction mixture was then concentrated to give compound 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (250 mg, crude) as a yellow oil, which was used in the next step without further purification. ESI-MS (M+H) + : 335.3.

11. 5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺的合成11. Synthesis of 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide

5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例2中8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯的合成。将残余物通过制备型HPLC(具有0.05％NH4HCO3的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺(120mg，产率：42％)。ESI-MS(M+H)+:487.3。1H NMR(400MHz,CD3OD)δ:8.43(d,J＝5.2Hz,1H),7.98-7.96(m,2H),7.51-7.30(m,3H),6.74(d,J＝2.4Hz,1H),5.44(d,J＝10.0Hz,1H),3.83(s,3H),3.09-3.03(m,2H),2.10-1.43(m,6H),1.54(s,9H)。The synthesis of 5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide was similar to that of 8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-4,5-dihydro-1H-benzo[c]azepine in Example 2 -2 (3H) -carboxylic acid tert-butyl ester. The residue was purified by preparative HPLC (CH 3 CN / H 2 O with 0.05% NH 4 HCO 3 as mobile phase) to give 5- (tert-butyl) -N- (2- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulene-5-yl) -1,2,4- oxadiazole-3-carboxamide (120 mg, yield: 42%) as a yellow solid. ESI-MS (M + H) + : 487.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.43 (d, J = 5.2Hz, 1H), 7.98-7.96 (m, 2H), 7.51-7.30 (m, 3H), 6.74 (d, J = 2.4Hz, 1H), 5.44 (d, J = 10.0Hz, 1H), 3.83 (s, 3H), 3.09 -3.03(m,2H),2.10-1.43(m,6H),1.54(s,9H).

实施例34.(R)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺(化合物34)Example 34. (R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (Compound 34)

1.(R,Z)-5-((1-苯基乙基)亚氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇的合成1. Synthesis of (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol

将2-羟基-6,7,8,9-四氢-5H-苯并[7]轮烯-5-酮(Herdman C.A.等人,Structuralinterrogation of benzosuberen-based inhibitors of tubulin polymerization,Bioorganic&Medical Chemistry,23(24),7497-7520,2015)(10g,57mmol)、(R)-(+)-α-甲基苄基胺(9.0g,74mmol)和对甲苯磺酸(0.48g,2.84mmol)于150mL甲苯中的浆料混合物用迪安斯塔克设备(Dean Stark apparatus)加热回流。16h之后，将迪安斯塔克设备移除并继续回流直至蒸馏出约80mL甲苯，在此期间固体结晶。将混合物冷却至0℃，保持在0℃2h，并且然后过滤，以得到呈棕褐色固体的(R,Z)-5-((1-苯基乙基)亚氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇(干燥之后，13.5g，产率：85％)。将粗产物用于下一步骤而无需进一步纯化。A slurry mixture of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-one (Herdman C.A. et al., Structural interrogation of benzosuberen-based inhibitors of tubulin polymerization, Bioorganic & Medical Chemistry, 23(24), 7497-7520, 2015) (10 g, 57 mmol), (R)-(+)-α-methylbenzylamine (9.0 g, 74 mmol) and p-toluenesulfonic acid (0.48 g, 2.84 mmol) in 150 mL of toluene was heated to reflux using a Dean Stark apparatus. After 16 h, the Dean Stark apparatus was removed and reflux was continued until about 80 mL of toluene was distilled off, during which time solid crystallized. The mixture was cooled to 0°C, kept at 0°C for 2 h, and then filtered to give (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol as a tan solid (after drying, 13.5 g, yield: 85%). The crude product was used in the next step without further purification.

2.(R)-5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇乙酸酯的合成2. Synthesis of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol acetate

将(R,Z)-5-((1-苯基乙基)亚氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇(13.5g,48mmol)于10:1EtOAc/MeOH(148mL)中的浆料冷却至-5℃。分批添加固体NaBH4(5.45g,144mmol)，同时维持温度低于5℃。在-5℃下将混合物搅拌40min。1h之后，添加水(135mL)，接着添加5N HCl直至pH为约6。分离各层，并且用135mL EtOAc萃取水层。将合并的有机物经盐水(100mL)洗涤并干燥(Na2SO4)并且过滤，以得到(R)-5-(((R)-1-苯基乙基)氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇溶液，将其向下进行。A slurry of (R,Z)-5-((1-phenylethyl)imino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol (13.5 g, 48 mmol) in 10:1 EtOAc/MeOH (148 mL) was cooled to -5°C. Solid NaBH4 (5.45 g, 144 mmol) was added portionwise while maintaining the temperature below 5°C. The mixture was stirred at -5°C for 40 min. After 1 h, water (135 mL) was added followed by 5N HCl until the pH was about 6. The layers were separated and the aqueous layer was extracted with 135 mL EtOAc. The combined organics were washed with brine (100 mL) and dried ( Na2SO4 ) and filtered to give a solution of (R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol which was carried forward.

向(R)-5-(((R)-1-苯基乙基)氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇(48mmol)于EtOAc(约185mL)中的溶液中添加乙酸(5.8g,96mmol)。然后将溶液浓缩并向下进行。To a solution of (R)-5-(((R)-1-phenylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol (48 mmol) in EtOAc (about 185 mL) was added acetic acid (5.8 g, 96 mmol). The solution was then concentrated and carried forward.

添加MeOH(200mL)，接着添加10％Pd/C(1.4g,10％wt％)。在55℃、H2(50psi)气氛下将混合物搅拌16h。将混合物过滤并将滤液浓缩。添加甲基叔丁基醚(100mL)，接着添加石油醚(100mL)。在25℃下将混合物搅拌2h并过滤。在50℃下干燥之后，分离出(R)-5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇乙酸酯(9.9g，产率：87％(三个步骤))。MeOH (200 mL) was added followed by 10% Pd/C (1.4 g, 10% wt%). The mixture was stirred at 55°C under H2 (50 psi) atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated. Methyl tert-butyl ether (100 mL) was added followed by petroleum ether (100 mL). The mixture was stirred at 25°C for 2 h and filtered. After drying at 50°C, (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol acetate (9.9 g, yield: 87% (three steps)) was isolated.

3.(R)-(2-羟基-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成3. Synthesis of tert-butyl (R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

向(R)-5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-醇乙酸酯(9.9g,42mmol)于二噁烷(50mL)中的溶液中添加水性NaHCO3(1N,100mL,100mmol)，接着添加Boc2O(13.7g,63mmol)。在室温下将混合物搅拌过夜。添加EtOAc(150mL)并将各层分离。用EtOAc(150mL)萃取水层。将合并的有机层干燥(Na2SO4)，过滤并浓缩。添加MTBE(150mL)，接着添加石油醚(150mL)。搅拌2h之后，将混合物过滤并将滤液浓缩以得到油状物。将粗物质通过硅胶色谱法纯化，以得到呈白色固体的(R)-(2-羟基-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(7.8g，产率：67％，ee：98.5％)。1H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),7.29-7.27(m,1H),6.94(d,J＝8.8Hz,1H),6.49(s,2H),4.48(m,1H),2.65(br s,2H),1.99-1.64(m,4H),1.48-1.25(m,11H)。To a solution of (R)-5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-ol acetate (9.9 g, 42 mmol) in dioxane (50 mL) was added aqueous NaHCO 3 (1 N, 100 mL, 100 mmol) followed by Boc 2 O (13.7 g, 63 mmol). The mixture was stirred overnight at room temperature. EtOAc (150 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated. MTBE (150 mL) was added followed by petroleum ether (150 mL). After stirring for 2 h, the mixture was filtered and the filtrate was concentrated to give an oil. The crude material was purified by silica gel chromatography to give tert-butyl (R)-(2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (7.8 g, yield: 67%, ee: 98.5%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.06 (s, 1H), 7.29-7.27 (m, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.49 (s, 2H), 4.48 (m, 1H), 2.65 (br s, 2H), 1.99-1.64 (m, 4H), 1.48-1.25 (m, 11H).

4.三氟甲烷磺酸(R)-5-((叔丁氧基羰基)氨基)-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基酯的合成4. Synthesis of (R)-5-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl trifluoromethanesulfonate

在0℃下向(R)-(2-羟基-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(1.0g,3.6mmol)和吡啶(570mg,7.2mmol)于DCM(30mL)中的溶液中添加Tf2O(1.5g,5.4mmol)。在0℃下将混合物搅拌1h。用水(20mL)稀释之后，用DCM(3×40mL)萃取混合物。将合并的有机层通过水性NaHSO4(0.5N,20mL)洗涤以将水层调整至pH＝5-6，干燥(Na2SO4)，过滤并浓缩。将粗产物用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:410.1。1H NMR(400MHz,CDCl3)δ:7.31(d,J＝8.8Hz,1H),7.07-7.00(m,2H),4.93-4.88(m,2H),2.89-2.82(m,2H),1.91-1.68(m,6H),1.45(s,9H)。To a solution of (R)-tert-butyl (2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate (1.0 g, 3.6 mmol) and pyridine (570 mg, 7.2 mmol) in DCM (30 mL) was added Tf 2 O (1.5 g, 5.4 mmol) at 0° C. The mixture was stirred for 1 h at 0° C. After dilution with water (20 mL), the mixture was extracted with DCM (3×40 mL). The combined organic layers were washed by aqueous NaHSO 4 (0.5 N, 20 mL) to adjust the aqueous layer to pH=5-6, dried (Na 2 SO 4 ), filtered and concentrated. The crude product was used in the next step without further purification. ESI-MS (M+H) + : 410.1. 1 H NMR (400MHz, CDCl 3 ) δ: 7.31 (d, J=8.8Hz, 1H), 7.07-7.00 (m, 2H), 4.93-4.88 (m, 2H), 2.89-2.82 (m, 2H), 1.91-1.68 (m, 6H), 1.45 (s, 9H).

5.(R)-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成5. Synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

(R)-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成类似于5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[c]氮杂-2(3H)-羧酸叔丁酯的合成(实施例2，步骤11)。将粗产物通过硅胶柱色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的(R)-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(420mg，产率68％)。ESI-MS(M+H)+:435.2。1H NMR(400MHz,CDCl3)δ:8.41-8.37(m,1H),7.88-7.77(m,3H),7.55-7.36(m,4H),7.05(d,J＝5.2Hz,1H),5.09-5.01(m,1H),3.90(s,3H),2.93-2.91(m,2H),2.18-2.17(m,1H),1.91-1.82(m,5H),1.28-1.24(m,9H)。The synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate was similar to that of 5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[c]azepine. -2 (3H) -carboxylic acid tert-butyl ester synthesis (Example 2, step 11). The crude product was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to give (R) - (2- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -6,7,8,9-tetrahydro-5H-benzo [7] annulene-5-yl) carbamic acid tert-butyl ester (420 mg, yield 68%) as a yellow solid. ESI-MS (M + H) + : 435.2. 1 H NMR (400MHz, CDCl 3 ) δ: 8.41-8.37 (m, 1H), 7.88-7.77 (m, 3H), 7.55-7.36 (m, 4H), 7.05 (d, J = 5.2Hz, 1H), 5.09-5.01 (m, 1H), 3.90 (s, 3H), 2.93-2.91 (m ,2H),2.18-2.17(m,1H),1.91-1.82(m,5H),1.28-1.24(m,9H).

6.(R)-4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成6. Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

(R)-4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺的合成类似于实施例2步骤12中所述的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成。将粗产物用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:335.2。The synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine was similar to that of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine as described in Step 12 of Example 2. The crude product was used in the next step without further purification. ESI-MS (M+H) + : 335.2.

7.(Z)-2-氨基-2-(((1-甲基环丙烷-1-羰基)氧基)亚氨基)乙酸乙酯的合成7. Synthesis of ethyl (Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetate

向1-甲基环丙烷-1-羧酸(2g,20mmol)于DCM(50mL)中的溶液中添加(COCl)2(5g,40mmol)。将混合物在室温下搅拌16h，然后浓缩以得到中间物酰氯。向(Z)-2-氨基-2-(羟基亚氨基)乙酸乙酯(2.6g,20mmol)和三乙胺(6g,60mmol)于DCM(20mL)中的溶液中添加中间物酰氯于DCM(20mL)中的溶液。在室温下将反应物搅拌2h，通过水洗涤，通过Na2SO4干燥，浓缩以得到呈白色固体的(Z)-2-氨基-2-(((1-甲基环丙烷-1-羰基)氧基)亚氨基)乙酸乙酯(3.0g，产率：63％)。ESI-MS(M+H)+:215.1。To a solution of 1-methylcyclopropane-1-carboxylic acid (2g, 20mmol) in DCM (50mL) was added (COCl) 2 (5g, 40mmol). The mixture was stirred at room temperature for 16h and then concentrated to give the intermediate acid chloride. To a solution of (Z)-2-amino-2-(hydroxyimino)ethyl acetate (2.6g, 20mmol) and triethylamine (6g, 60mmol) in DCM (20mL) was added a solution of the intermediate acid chloride in DCM (20mL). The reactant was stirred at room temperature for 2h, washed with water, dried over Na 2 SO 4 , and concentrated to give (Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)ethyl acetate (3.0g, yield: 63%) as a white solid. ESI-MS (M+H) + : 215.1.

8. 5-(1-甲基环丙基)-1,2,4-噁二唑-3-羧酸乙酯的合成8. Synthesis of ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate

在100℃下将(Z)-2-氨基-2-(((1-甲基环丙烷-1-羰基)氧基)亚氨基)乙酸乙酯(3.0g,14mmol)于AcOH(20mL)中的溶液搅拌2h然后浓缩。将残余物用DCM(20mL)稀释，通过饱和NaHCO3溶液(3×10mL)洗涤，经Na2SO4干燥并浓缩。将残余物通过硅胶柱(石油醚:EtOAc＝10:1)纯化，以得到呈黄色固体的5-(1-甲基环丙基)-1,2,4-噁二唑-3-羧酸乙酯(1.1g，产率：52％)。ESI-MS(M+H)+:197.1。A solution of (Z)-2-amino-2-(((1-methylcyclopropane-1-carbonyl)oxy)imino)acetic acid ethyl ester (3.0 g, 14 mmol) in AcOH (20 mL) was stirred at 100 ° C for 2 h and then concentrated. The residue was diluted with DCM (20 mL), washed with saturated NaHCO 3 solution (3×10 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column (petroleum ether:EtOAc=10:1) to give ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.1 g, yield: 52%) as a yellow solid. ESI-MS (M+H) + : 197.1.

9. 5-(1-甲基环丙基)-1,2,4-噁二唑-3-羧酸钾的合成9. Synthesis of Potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate

将5-(1-甲基环丙基)-1,2,4-噁二唑-3-羧酸乙酯(1.0g,5.0mmol)和KOH(308mg,5.5mmol)溶解于EtOH/H2O(4:1,20mL)中。将反应物在室温下搅拌12h然后浓缩以得到呈黄色固体的5-(1-甲基环丙基)-1,2,4-噁二唑-3-羧酸钾(1.1g，产率：95％)。ESI-MS(M+H)+:169.1。Ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.0 g, 5.0 mmol) and KOH (308 mg, 5.5 mmol) were dissolved in EtOH/H 2 O (4:1, 20 mL). The reaction was stirred at room temperature for 12 h and then concentrated to give potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.1 g, yield: 95%) as a yellow solid. ESI-MS (M+H) + : 169.1.

10.N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺(I-IM_6)的合成10. Synthesis of N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (I-IM_6)

向5-(1-甲基环丙基)-1,2,4-噁二唑-3-羧酸钾(123mg,0.6mmol)、DIPEA(232mg,0.75mmol)和HATU(342mg,0.9mmol)于DCM(5mL)中的溶液中添加(R)-4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(150mg,0.50mmol)。在室温下将混合物搅拌1h。用水(60mL)稀释之后，用DCM(80mL×2)萃取混合物。将合并的有机层干燥并浓缩。将粗产物通过制备型HPLC纯化，以得到呈白色固体的(R)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺(60mg，产率：30％)。ESI-MS(M+H)+:485.2。1H NMR(400MHz,CD3OD)δ:8.40(d,J＝5.2Hz,1H),7.97(s,1H),7.98-7.93(m,2H),7.66(s,1H),7.39(d,J＝8.4Hz,1H),7.21(d,J＝5.2Hz,1H),5.43(d,J＝10Hz,1H),3.90(s,3H),3.09-3.02(m,2H),2.09-1.86(m,5H),1.64(s,3H),1.54-1.45(m,3H),1.21-1.18(m,2H)。To a solution of potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (123 mg, 0.6 mmol), DIPEA (232 mg, 0.75 mmol) and HATU (342 mg, 0.9 mmol) in DCM (5 mL) was added (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (150 mg, 0.50 mmol). The mixture was stirred at room temperature for 1 h. After dilution with water (60 mL), the mixture was extracted with DCM (80 mL×2). The combined organic layers were dried and concentrated. The crude product was purified by preparative HPLC to give (R)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (60 mg, yield: 30%) as a white solid. ESI-MS (M+H) + : 485.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.40 (d, J = 5.2Hz, 1H), 7.97 (s, 1H), 7.98-7.93 (m, 2H), 7.66 (s, 1H), 7.39 (d, J = 8.4Hz, 1H), 7.21 (d, J = 5.2Hz, 1H), 5.43 (d, J = 1 0Hz,1H),3.90(s,3H),3.09-3.02(m,2H),2.09-1.86(m,5H),1.64(s,3H),1.54-1.45(m,3H),1.21-1.18(m,2H).

实施例35.(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺(化合物35)Example 35. (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 35)

1.(R)-(2-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成1. Synthesis of tert-butyl (R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

(R)-(2-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成类似于1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯的合成(实施例1，步骤12)。将粗物质通过硅胶柱色谱法(MeOH/EtOAc＝1/50)纯化，以得到呈黄色固体的(R)-(2-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(350mg，产率：44％)。ESI-MS(M+H)+:373.2。The synthesis of tert-butyl (R)-(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate was similar to that of 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine -3 (2H) -carboxylic acid tert-butyl ester synthesis (Example 1, step 12). The crude material was purified by silica gel column chromatography (MeOH / EtOAc = 1 / 50) to give a yellow solid (R) - (2- (2-chloropyridin-4-yl) -6,7,8,9-tetrahydro -5H-benzo [7] annulene -5-yl) carbamic acid tert-butyl ester (350 mg, yield: 44%). ESI-MS (M + H) + : 373.2.

2.(R)-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成2. Synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)carbamate

向(R)-(2-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(400mg,1.1mmol)于二噁烷(20mL)中的溶液中添加1-甲基-1H-吡唑-4-胺(210mg,2.1mmol)、Pd2(dba)3(100mg,0.11mmol)、SPhos(45mg,0.11mmol)和Cs2CO3(680mg,2.1mmol)。将混合物加热至100℃持续2h并浓缩。将粗物质通过硅胶柱色谱法(MeOH/EtOAc＝1/50)纯化，以得到呈黄色固体的(R)-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯(330mg，产率：71％)。ESI-MS(M+H)+:434.2。To a solution of (R)-tert-butyl(2-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (400 mg, 1.1 mmol) in dioxane (20 mL) was added 1-methyl-1H-pyrazol-4-amine (210 mg, 2.1 mmol), Pd2 ( dba ) 3 (100 mg, 0.11 mmol), SPhos (45 mg, 0.11 mmol) and Cs2CO3 (680 mg, 2.1 mmol). The mixture was heated to 100°C for 2 h and concentrated. The crude material was purified by silica gel column chromatography (MeOH/EtOAc=1/50) to give tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (330 mg, yield: 71%) as a yellow solid. ESI-MS (M+H) + : 434.2.

3.(R)-4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)吡啶-2-胺的合成3. Synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine

(R)-4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)吡啶-2-胺的合成类似于5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺的合成(实施例1，步骤13)。获得呈黄色固体的粗产物(R)-4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)吡啶-2-胺(200mg，产率：79％)。ESI-MS(M+H)+:334.2。The synthesis of (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine was similar to that of 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. -1-yl)-1,2,4-oxadiazole-3-carboxamide (Example 1, Step 13). The crude product (R)-4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (200 mg, yield: 79%) was obtained as a yellow solid. ESI-MS (M+H) + : 334.2.

4.(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺(I-IM_65)的合成4. Synthesis of (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide (I-IM_65)

(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例34步骤10中N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-5-(1-甲基环丙基)-1,2,4-噁二唑-3-甲酰胺的合成。将混合物通过制备型HPLC(具有0.05％NH3.H2O的CH3CN/H2O作为流动相)纯化，以得到呈黄色固体的(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-3-甲酰胺(100mg，产率：88％)。ESI-MS(M+H)+:486.3。1H NMR(400MHz,CDCl3)δ:8.17-8.16(m,1H),7.61(s,1H),7.48(s,1H),7.43-7.41(m,1H),7.36-7.30(m,3H),6.87-6.86(m,1H),6.71(s,1H),6.22-6.18(m,1H),5.44-5.40(m,1H),3.91(s,3H),3.01-2.89(m,2H),2.05-1.93(m,4H),1.82-1.78(m,2H),1.49(s,9H)。The synthesis of (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-3-carboxamide is similar to the synthesis of N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide in step 10 of Example 34. The mixture was purified by preparative HPLC ( CH3CN /H2O with 0.05% NH3.H2O as mobile phase) to give (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide (100 mg, yield: 88%) as a yellow solid. ESI-MS (M+H) + : 486.3. 1 H NMR (400MHz, CDCl 3 )δ:8.17-8.16(m,1H),7.61(s,1H),7.48(s,1H),7.43-7.41(m,1H),7.36-7.30(m,3H),6.87-6.86(m,1H),6.71(s,1H),6.22-6 .18(m,1H),5.44-5.40(m,1H),3.91(s,3H),3.01-2.89(m,2H),2.05-1.93(m,4H),1.82-1.78(m,2H),1.49(s,9H).

实施例36.(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物36a)Example 36. (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 36a)

1.(R)-1-(叔丁基)-N-(8-(2-氯嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂5-基)-1H-1,2,3-三唑-4-甲酰胺的合成1. (R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 5-hydroxy-1H-1,2,3-triazole-4-carboxamide

(R)-1-(叔丁基)-N-(8-(2-氯嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于(R)-5-(叔丁基)-N-(8-(2-((1,5-二甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[c]氮杂-5-基)-1,2,4-噁二唑-3-甲酰胺的合成(实施例9，步骤4)。将粗产物用于下一步骤而无需纯化。ESI-MS(M+H)+:427.2。(R)-1-(tert-butyl)-N-(8-(2-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine The synthesis of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was similar to that of (R)-5-(tert-butyl)-N-(8-(2-((1,5-dimethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine Synthesis of 1-(5-yl)-1,2,4-oxadiazole-3-carboxamide (Example 9, Step 4). The crude product was used in the next step without purification. ESI-MS (M+H) + : 427.2.

2.(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物36a)和(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物36b)的合成2. Synthesis of (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 36a) and (S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 36b)

使3-叔丁基-1,2,4-噁二唑-5-羧酸{2-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-6,7,8,9-四氢-5H-苯并环庚-5-基}-酰胺(76mg)经历SFC分离(IA 2x(2×15cm)，30％乙醇/CO2，100巴，70mL/min，220nm，注射体积：1mL，5mg/mL，乙醇)并产生43mg峰1(化学纯度99％，ee>99％)和36mg峰2(化学纯度99％，ee>99％)。3-tert-Butyl-1,2,4-oxadiazole-5-carboxylic acid {2-[2-(1-methyl-1H-pyrazol-4-ylamino)-pyrimidin-4-yl]-6,7,8,9-tetrahydro-5H-benzosuber-5-yl}-amide (76 mg) was subjected to SFC separation (IA 2x(2×15 cm), 30% ethanol/CO 2 , 100 bar, 70 mL/min, 220 nm, injection volume: 1 mL, 5 mg/mL, ethanol) and produced 43 mg of peak 1 (chemical purity 99%, ee>99%) and 36 mg of peak 2 (chemical purity 99%, ee>99%).

峰1被指定为(R)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺：LCMS:Rt 1.23min，m/z 487.00。1H NMR(400MHz,甲醇-d4)δ8.41(d,J＝5.27Hz,1H),7.96(d,J＝11.80Hz,3H),7.66(s,1H),7.43(d,J＝8.53Hz,1H),7.22(d,J＝5.27Hz,1H),5.43(d,J＝9.29Hz,1H),3.90(s,3H),2.96-3.24(m,2H),1.74-2.25(m,5H),1.51(s,9H),1.28-1.43(m,1H)。Peak 1 was assigned to (R)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide: LCMS: Rt 1.23 min, m/z 487.00. 1 H NMR (400MHz, methanol-d4) δ8.41 (d, J = 5.27Hz, 1H), 7.96 (d, J = 11.80Hz, 3H), 7.66 (s, 1H), 7.43 (d, J = 8.53Hz, 1H), 7.22 (d, J = 5.27Hz, 1H), 5.43 (d, J = 9.29Hz, 1H),3.90(s,3H),2.96-3.24(m,2H),1.74-2.25(m,5H),1.51(s,9H),1.28-1.43(m,1H).

峰2被指定为(S)-5-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,3,4-噁二唑-2-甲酰胺：LCMS:Rt 1.23min，m/z 487.00。1H NMR(400MHz,甲醇-d4)δ8.40(d,J＝5.27Hz,1H),7.96(d,J＝12.05Hz,3H),7.66(s,1H),7.43(d,J＝8.53Hz,1H),7.22(d,J＝5.27Hz,1H),5.44(s,1H),3.90(s,3H),2.93-3.21(m,2H),1.78-2.23(m,5H),1.51(s,9H),1.31(s,1H)。Peak 2 was assigned to (S)-5-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,3,4-oxadiazole-2-carboxamide: LCMS: Rt 1.23 min, m/z 487.00. 1 H NMR (400MHz, methanol-d4) δ8.40(d,J＝5.27Hz,1H),7.96(d,J＝12.05Hz,3H),7.66(s,1H),7.43(d,J＝8.53Hz,1H),7.22(d,J＝5.27Hz,1H),5.44(s,1H),3.90 (s,3H),2.93-3.21(m,2H),1.78-2.23(m,5H),1.51(s,9H),1.31(s,1H).

实施例37. 3-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-5-甲酰胺(化合物37)Example 37. 3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-5-yl)-1,2,4-oxadiazole-5-carboxamide (Compound 37)

向3-叔丁基-1,2,4-噁二唑-5-羧酸(1.00mg,0.60mmol)和N,N,N',N'-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(273mg,0.72mmol)和4-(5-氨基-6,7,8,9-四氢-5H-苯并[7]轮烯-2-基)-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(200mg,0.6mmol)于N,N-二甲基甲酰胺(2.3mL)中的溶液中添加N,N-二异丙基乙基胺(0.42mL,2.4mmol)。将反应物在室温下搅拌过夜并用MeOH淬灭。处理之后，制备型HPLC得到呈固体的3-(叔丁基)-N-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)-1,2,4-噁二唑-5-甲酰胺(186mg；产率：64％)。LCMS:Rt 1.38min.；m/z 487.1；1H NMR(400MHz,甲醇-d4)δ:8.29(br.s.,1H),7.97-8.09(m,2H),7.94(s,1H),7.68(br.s.,1H),7.43(d,J＝8.78Hz,2H),5.41(d,J＝9.79Hz,1H),3.92(s,3H),2.87-3.18(m,2H),1.70-2.29(m,5H),1.45(s,10H)。To a solution of 3-tert-butyl-1,2,4-oxadiazole-5-carboxylic acid (1.00 mg, 0.60 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (273 mg, 0.72 mmol) and 4-(5-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (200 mg, 0.6 mmol) in N,N-dimethylformamide (2.3 mL) was added N,N-diisopropylethylamine (0.42 mL, 2.4 mmol). The reaction was stirred at room temperature overnight and quenched with MeOH. After work-up, preparative HPLC afforded 3-(tert-butyl)-N-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-5-carboxamide (186 mg; yield: 64%) as a solid. LCMS: Rt 1.38min.; m/z 487.1; 1 H NMR (400MHz, methanol-d4) δ: 8.29 (br.s., 1H), 7.97-8.09 (m, 2H), 7.94 (s, 1H), 7.68 (br.s., 1H), 7.43 (d, J = 8.78Hz, 2H), 5.41 (d,J=9.79Hz,1H),3.92(s,3H),2.87-3.18(m,2H),1.70-2.29(m,5H),1.45(s,10H).

实施例38：5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,3,4-噁二唑-2-甲酰胺(化合物38)Example 38: 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 38)

1. 4-(3-溴苯氧基)丁酸甲酯1. Methyl 4-(3-bromophenoxy)butyrate

向3-溴苯酚(3.44g,20.0mmol)和4-溴丁酸甲酯(4.32g,24.0mmol)于DMF(20mL)中的溶液中添加K2CO3(5.52g,40.0mmol)。将混合物在室温下搅拌0.5h，然后在搅拌的同时在90℃下加热1h。用EtOAc(200mL)稀释之后，将混合物用水(3×50mL)洗涤，干燥并浓缩。将粗产物通过硅胶柱色谱法(石油/EtOAc＝10:1)纯化，以得到呈白色液体的4-(3-溴苯氧基)丁酸甲酯(5.2g，产率：96％)。ESI-MS(M+H)+:273.1。To a solution of 3-bromophenol (3.44 g, 20.0 mmol) and methyl 4-bromobutyrate (4.32 g, 24.0 mmol) in DMF (20 mL) was added K 2 CO 3 (5.52 g, 40.0 mmol). The mixture was stirred at room temperature for 0.5 h and then heated at 90 ° C for 1 h while stirring. After dilution with EtOAc (200 mL), the mixture was washed with water (3×50 mL), dried and concentrated. The crude product was purified by silica gel column chromatography (petroleum/EtOAc=10:1) to give methyl 4-(3-bromophenoxy)butyrate (5.2 g, yield: 96%) as a white liquid. ESI-MS (M+H) + : 273.1.

2. 4-(3-溴苯氧基)丁酸的合成2. Synthesis of 4-(3-bromophenoxy)butyric acid

向4-(3-溴苯氧基)丁酸甲酯(4.9g,19mmol)于MeOH(40mL)和H2O(40mL)中的溶液中添加NaOH(2.3g,57mmol)。在65℃下将反应混合物搅拌1h。然后将溶剂在减压下浓缩。用HCl(1N)将残余物调整至pH＝3。用EtOAc(3×100mL×3)萃取混合物。将有机层经硫酸钠干燥并在减压下浓缩，以得到4-(3-溴苯氧基)丁酸(4.8g，产率：98％)。将粗产物用于下一步骤而无需进一步纯化。ESI-MS(M+H)+:259.1。1H NMR(400MHz,CDCl3)δ:7.24-7.20(m,1H),7.10-7.08(m,2H),6.93(d,J＝9.6Hz,1H),3.97(t,J＝6.4Hz,2H),2.35(t,J＝7.2Hz,2H),1.92-1.88(m,2H)。To a solution of methyl 4-(3-bromophenoxy)butyrate (4.9 g, 19 mmol) in MeOH (40 mL) and H 2 O (40 mL) was added NaOH (2.3 g, 57 mmol). The reaction mixture was stirred at 65° C. for 1 h. The solvent was then concentrated under reduced pressure. The residue was adjusted to pH=3 with HCl (1 N). The mixture was extracted with EtOAc (3×100 mL×3). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 4-(3-bromophenoxy)butyric acid (4.8 g, yield: 98%). The crude product was used in the next step without further purification. ESI-MS (M+H) + :259.1. 1 H NMR (400MHz, CDCl 3 ) δ: 7.24-7.20 (m, 1H), 7.10-7.08 (m, 2H), 6.93 (d, J = 9.6 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 1.92-1.88 (m, 2H).

3. 8-溴-3,4-二氢苯并[b]氧杂环庚三烯基-5(2H)-酮的合成3. Synthesis of 8-bromo-3,4-dihydrobenzo[b]oxepanyl-5(2H)-one

向4-(3-溴苯氧基)丁酸(1.82g,7.04mmol)于DCM(35mL)中的溶液中添加SOCl2(1.67g,14mmol)和DMF(催化剂)。将反应混合物在40℃下搅拌1h。然后将溶剂在减压下移除，在真空中干燥2h。将残余物溶解于DCM(35mL)中并用冰浴冷却。添加AlCl3(1.02g,80mmol)，并且在0℃-室温下将混合物搅拌12h。将混合物倾倒至浓HCl(10mL)中并用EtOAc(2×50mL)萃取。将有机层用水(50mL)、盐水(50mL)洗涤，并且经硫酸钠干燥。在减压下浓缩之后，将粗产物通过硅胶柱色谱法(石油醚/EtOAc＝4:1)纯化，以得到呈白色固体的8-溴-3,4-二氢苯并[b]氧杂环庚三烯基-5(2H)-酮(1.2g，产率：71％)。ESI-MS(M+H)+:241.1。1HNMR(400MHz,CDCl3)δ:7.64(d,J＝8.8Hz,1H),7.27-7.23(m,2H),4.25(t,J＝6.8Hz,2H),2.89(t,J＝7.2Hz,2H),2.25-2.18(m,2H)。To a solution of 4-(3-bromophenoxy)butyric acid (1.82 g, 7.04 mmol) in DCM (35 mL) was added SOCl 2 (1.67 g, 14 mmol) and DMF (catalyst). The reaction mixture was stirred at 40 °C for 1 h. The solvent was then removed under reduced pressure and dried in vacuo for 2 h. The residue was dissolved in DCM (35 mL) and cooled with an ice bath. AlCl 3 (1.02 g, 80 mmol) was added, and the mixture was stirred at 0 °C-room temperature for 12 h. The mixture was poured into concentrated HCl (10 mL) and extracted with EtOAc (2×50 mL). The organic layer was washed with water (50 mL), brine (50 mL), and dried over sodium sulfate. After concentration under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give 8-bromo-3,4-dihydrobenzo[b]oxepinyl-5(2H)-one (1.2 g, yield: 71%) as a white solid. ESI-MS (M+H) + : 241.1. 1 HNMR (400 MHz, CDCl 3 ) δ: 7.64 (d, J=8.8 Hz, 1H), 7.27-7.23 (m, 2H), 4.25 (t, J=6.8 Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.25-2.18 (m, 2H).

4. 8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-胺的合成4. Synthesis of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-ylamine

向8-溴-3,4-二氢苯并[b]氧杂环庚三烯基-5(2H)-酮(1.2g,5.0mmol)于i-PrOH(50mL)中的溶液中添加NH4OAc(7.63g,100mmol)和NaBH3CN(3.15g,50mol)。在80℃下将混合物搅拌4h。冷却之后，用NaOH(1N)将混合物碱化至pH>12。用DCM(250mL×2)萃取混合物。将合并的有机层干燥并浓缩。将所得残余物通过硅胶柱(DCM:MeOH＝20:1)纯化，以得到呈白色固体的8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-胺(900mg，产率：75％)。ESI-MS(M+H-NH3)+:225.1。To a solution of 8-bromo-3,4-dihydrobenzo[b]oxepinyl-5(2H)-one (1.2 g, 5.0 mmol) in i-PrOH (50 mL) was added NH 4 OAc (7.63 g, 100 mmol) and NaBH 3 CN (3.15 g, 50 mol). The mixture was stirred at 80° C. for 4 h. After cooling, the mixture was basified to pH>12 with NaOH (1 N). The mixture was extracted with DCM (250 mL×2). The combined organic layers were dried and concentrated. The resulting residue was purified by silica gel column (DCM:MeOH=20:1) to give 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepinyl-5-amine (900 mg, yield: 75%) as a white solid. ESI-MS (M+H-NH 3 ) + :225.1.

5.N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺的合成5. Synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide

向8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-胺(500mg,2.23mmol,1.0当量)于DMF(20mL)中的溶液中添加5-叔丁基-1,3,4-噁二唑-2-羧酸钾(557mg,2.68mmol,1.2当量)、HATU(1.3g,3.35mmol,1.5当量)和三乙胺(863mg,6.69mmol,3.0当量)。在室温下将混合物搅拌2h。将溶液用EtOAc(150mL)稀释并用水(50mL)、盐水(2×50mL)洗涤。将有机层干燥(Na2SO4)，过滤，并且经由旋转蒸发器浓缩。将残余物通过反相色谱法(具有0.05％NH3.H2O的CH3CN/H2O作为流动相)纯化，以得到呈淡黄色固体的N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺(210mg，产率：30％)。ESI-MS(M+H)+:394.1。To a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepinyl-5-amine (500 mg, 2.23 mmol, 1.0 equiv) in DMF (20 mL) was added potassium 5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (557 mg, 2.68 mmol, 1.2 equiv), HATU (1.3 g, 3.35 mmol, 1.5 equiv) and triethylamine (863 mg, 6.69 mmol, 3.0 equiv). The mixture was stirred at room temperature for 2 h. The solution was diluted with EtOAc (150 mL) and washed with water (50 mL), brine (2×50 mL). The organic layer was dried (Na 2 SO 4 ), filtered, and concentrated via rotary evaporator. The residue was purified by reverse phase chromatography ( CH3CN / H2O with 0.05% NH3.H2O as mobile phase) to give N-(8-bromo-2,3,4,5- tetrahydrobenzo [b]oxepin-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide (210 mg, yield: 30%) as a light yellow solid. ESI-MS (M+H) + : 394.1.

6. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,3,4-噁二唑-2-甲酰胺的制备6. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide

在N2下向N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,3,4-噁二唑-2-甲酰胺(393mg,1.00mmol)和PinB-BPin(263mg,1.1mmol)于无水1,4-二噁烷(10mL)中的混合物中添加KOAc(196mg,2.0mmol)、Pd(dppf)Cl2.DCM(81mg,0.1mmol)。在100℃、N2下将混合物搅拌2h。冷却之后，添加4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(209mg,1.0mmol)、K2CO3(276mg,2.0mmol)和H2O(2.5mL)。在100℃、N2下将混合物搅拌2h。冷却之后，将混合物浓缩并通过硅胶柱色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,3,4-噁二唑-2-甲酰胺(50mg，产率：21％)。ESI-MS(M+H)+:489.2。1H NMR(400MHz,CD3OD)δ:8.26(d,J＝5.2Hz,1H),7.82(s,1H),7.69-7.64(m,2H),7.51(s,1H),7.29(d,J＝8.0Hz,1H),7.02(d,J＝5.2Hz,1H),5.35-5.32(m,1H),4.14-4.10(m,1H),3.83-3.80(m,1H),3.76(s,3H),2.00-1.98(m,4H),1.36(s,9H)。To a mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepinyl-5-yl)-5-(tert-butyl)-1,3,4-oxadiazole-2-carboxamide (393 mg, 1.00 mmol) and PinB-BPin (263 mg, 1.1 mmol) in anhydrous 1,4-dioxane (10 mL) was added KOAc (196 mg, 2.0 mmol), Pd(dppf)Cl 2 .DCM (81 mg, 0.1 mmol) under N 2. The mixture was stirred at 100° C. under N 2 for 2 h. After cooling, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (209 mg, 1.0 mmol), K 2 CO 3 (276 mg, 2.0 mmol) and H 2 O (2.5 mL) were added. The mixture was stirred at 100° C. under N 2 for 2 h. After cooling, the mixture was concentrated and purified by silica gel column chromatography (DCM/MeOH=20:1) to give 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,3,4-oxadiazole-2-carboxamide (50 mg, yield: 21%) as a yellow solid. ESI-MS (M+H) + : 489.2. 1 H NMR (400MHz, CD 3 OD) δ: 8.26 (d, J = 5.2Hz, 1H), 7.82 (s, 1H), 7.69-7.64 (m, 2H), 7.51 (s, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.02 (d, J = 5.2Hz, 1H), 5.35-5.32 ( m,1H),4.14-4.10(m,1H),3.83-3.80(m,1H),3.76(s,3H),2.00-1.98(m,4H),1.36(s,9H).

实施例39. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,2,4-噁二唑-2-甲酰胺(化合物39)的合成Example 39. Synthesis of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide (Compound 39)

1.N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,2,4-噁二唑-2-甲酰胺的合成1. Synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide

N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,2,4-噁二唑-3-甲酰胺的合成类似于实施例2方法2步骤2中(R)-8-溴-5-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-1,3,4,5-四氢-2H-苯并[c]氮杂-2-羧酸叔丁酯的合成。将粗物质通过硅胶色谱法(PE:EtOAc＝3:1)纯化，以得到呈淡黄色固体的N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,2,4-噁二唑-2-甲酰胺(610mg，产率：85％)。ESI-MS(M+H)+:394.1。The synthesis of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide was similar to that of (R)-8-bromo-5-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-1,3,4,5-tetrahydro-2H-benzo[c]azepine in step 2 of method 2 of example 2. -2-carboxylic acid tert-butyl ester. The crude material was purified by silica gel chromatography (PE: EtOAc = 3: 1) to give N- (8-bromo-2,3,4,5-tetrahydrobenzo [b] oxepinyl -5-yl) -5- (tert-butyl) -1,2,4- oxadiazole -2-carboxamide (610 mg, yield: 85%) as a light yellow solid. ESI-MS (M + H) + : 394.1.

2. 5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,2,4-噁二唑-2-甲酰胺的制备2. Preparation of 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide

在N2下向N-(8-溴-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-5-(叔丁基)-1,2,4-噁二唑-2-甲酰胺(135mg,0.34mmol)和PinB-BPin(96mg,0.38mmol)于无水1,4-二噁烷(3mL)中的混合物中添加KOAc(68mg,0.69mmol)、Pd(dppf)Cl2.DCM(24mg,0.03mmol)。在100℃、N2下将混合物搅拌2h。冷却之后，添加4-氯-N-(1-甲基-1H-吡唑-4-基)嘧啶-2-胺(71mg,0.34mmol)、K2CO3(95mg,0.69mmol)和H2O(0.8mL)。在100℃、N2下将混合物搅拌2h。冷却之后，将混合物浓缩并通过硅胶色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-(8-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢苯并[b]氧杂环庚三烯基-5-基)-1,2,4-噁二唑-2-甲酰胺(77mg，产率：46％)。ESI-MS(M+H)+:489.2。1HNMR(400MHz,CD3OD)δ:8.35(d,J＝5.2Hz,1H),7.91(s,1H),7.78-7.73(m,2H),7.62(s,1H),7.38(d,J＝8.4Hz,1H),7.10(d,J＝5.6Hz,1H),5.46-5.44(m,1H),4.18-4.15(m,1H),3.98-3.95(m,1H),3.86(s,3H),2.10-2.02(m,4H),1.48(s,9H)。To a mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepinyl-5-yl)-5-(tert-butyl)-1,2,4-oxadiazole-2-carboxamide (135 mg, 0.34 mmol) and PinB-BPin (96 mg, 0.38 mmol) in anhydrous 1,4-dioxane (3 mL) was added KOAc (68 mg, 0.69 mmol), Pd(dppf)Cl 2 .DCM (24 mg, 0.03 mmol) under N 2. The mixture was stirred at 100° C. under N 2 for 2 h. After cooling, 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (71 mg, 0.34 mmol), K 2 CO 3 (95 mg, 0.69 mmol) and H 2 O (0.8 mL) were added. The mixture was stirred at 100° C. under N 2 for 2 h. After cooling, the mixture was concentrated and purified by silica gel chromatography (DCM/MeOH=20:1) to give 5-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-1,2,4-oxadiazole-2-carboxamide (77 mg, yield: 46%) as a yellow solid. ESI-MS (M+H) + : 489.2. 1 HNMR (400MHz, CD 3 OD) δ: 8.35 (d, J = 5.2Hz, 1H), 7.91 (s, 1H), 7.78-7.73 (m, 2H), 7.62 (s, 1H), 7.38 (d, J = 8.4Hz, 1H), 7.10 (d, J = 5.6Hz, 1H), 5.46-5.44 ( m,1H),4.18-4.15(m,1H),3.98-3.95(m,1H),3.86(s,3H),2.10-2.02(m,4H),1.48(s,9H).

实施例40. 5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺(化合物40)Example 40. 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 40)

1. 3-氯环庚-2-烯-1-酮的合成1. Synthesis of 3-chlorocyclohept-2-en-1-one

在0℃下向环庚-1,3-二酮(20.0g,0.16mol)和DMF(11.6g,0.16mol)于DCM(500mL)中的溶液中逐滴添加草酰氯(24.4g,0.19mol)。在0℃下搅拌30min之后，用水(3×500mL)洗涤反应混合物。然后用乙醚(4×300mL)萃取水相。将合并的DCM和乙醚相经MgSO4干燥并浓缩，以产生呈棕色油状物的3-氯环庚-2-烯-1-酮(粗物质22.8g，用于下一步骤)。ESI-MS(M+H)+:145.1。To a solution of cycloheptane-1,3-dione (20.0 g, 0.16 mol) and DMF (11.6 g, 0.16 mol) in DCM (500 mL) was added oxalyl chloride (24.4 g, 0.19 mol) dropwise at 0 ° C. After stirring at 0 ° C for 30 min, the reaction mixture was washed with water (3×500 mL). The aqueous phase was then extracted with ether (4×300 mL). The combined DCM and ether phases were dried over MgSO 4 and concentrated to give 3-chlorocycloheptane-2-ene-1-one (crude material 22.8 g, used in the next step) as a brown oil. ESI-MS (M+H) + : 145.1.

2. 2-氰基-2-(3-氧代环庚-1-烯-1-基)乙酰胺的合成2. Synthesis of 2-cyano-2-(3-oxocyclohept-1-en-1-yl)acetamide

在0℃下一次性向2-氰基乙酰胺(26.9g,0.32mol)于DMF(300mL)中的溶液中添加NaH(60百分比于矿物油中，14.1g，0.35mol)。在0℃下搅拌30min之后，逐滴添加3-氯环庚-2-烯-1-酮(22.8g,0.16mol)于DMF(100mL)中的溶液。在室温下将反应混合物搅拌30min，并且在减压下移除DMF。将残余物溶解于水(350mL)中。将溶液用乙酸乙酯(4×150mL)洗涤，用3.0N HCl水溶液调整至pH 2-3并用10％MeOH/DCM(6×300mL)萃取。将后来合并的萃取物经MgSO4干燥并浓缩。将粗产物通过硅胶柱色谱法(EtOAc/石油醚＝4:1)纯化，以得到呈黄色油状物的2-氰基-2-(3-氧代环庚-1-烯-1-基)乙酰胺(22.0g，产率73％(两个步骤))。ESI-MS(M+H)+:193.1。To a solution of 2-cyanoacetamide (26.9 g, 0.32 mol) in DMF (300 mL) was added NaH (60 percent in mineral oil, 14.1 g, 0.35 mol) at 0°C in one portion. After stirring at 0°C for 30 min, a solution of 3-chlorocyclohept-2-ene-1-one (22.8 g, 0.16 mol) in DMF (100 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, and DMF was removed under reduced pressure. The residue was dissolved in water (350 mL). The solution was washed with ethyl acetate (4×150 mL), adjusted to pH 2-3 with 3.0 N aqueous HCl solution and extracted with 10% MeOH/DCM (6×300 mL). The combined extracts were dried over MgSO 4 and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether=4:1) to give 2-cyano-2-(3-oxocyclohept-1-en-1-yl)acetamide (22.0 g, yield 73% (two steps)) as a yellow oil. ESI-MS (M+H) + : 193.1.

3. 3,9-二氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-4-甲腈的合成3. Synthesis of 3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridine-4-carbonitrile

在0.5h内向2-氰基-2-(3-氧代环庚-1-烯-1-基)乙酰胺(22.0g,0.11mol)于DMF(150mL)中的溶液中逐滴添加DMF-DMA(22.8mL,0.17mol)。将反应混合物在50℃下搅拌4h并在减压下浓缩。将所得棕色油状物溶解于NaOH水溶液(1.0N,200mL)中，用氯仿(5×150mL)洗涤，并且在0℃下用HCl(6.0N)缓慢酸化至pH 2-3。将棕色固体3,9-二氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-4-甲腈(17.0g，产率：74％)通过过滤收集并在真空中干燥。ESI-MS(M+H)+:203.1。1H NMR(400MHz,CDCl3)δ:8.16(s,1H),3.17-3.14(m,2H),2.77-2.74(m,2H),2.04-2.00(m,2H),1.90-1.87(m,2H)。DMF-DMA (22.8 mL, 0.17 mol) was added dropwise to a solution of 2-cyano-2-(3-oxocyclohept-1-ene-1-yl)acetamide (22.0 g, 0.11 mol) in DMF (150 mL) within 0.5 h. The reaction mixture was stirred at 50 ° C for 4 h and concentrated under reduced pressure. The resulting brown oil was dissolved in an aqueous NaOH solution (1.0 N, 200 mL), washed with chloroform (5 × 150 mL), and slowly acidified to pH 2-3 with HCl (6.0 N) at 0 ° C. The brown solid 3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cycloheptyl[c]pyridine-4-carbonitrile (17.0 g, yield: 74%) was collected by filtration and dried in vacuo. ESI-MS (M+H) + : 203.1. 1 H NMR (400MHz, CDCl 3 ) δ: 8.16 (s, 1H), 3.17-3.14 (m, 2H), 2.77-2.74 (m, 2H), 2.04-2.00 (m, 2H), 1.90-1.87 (m, 2H).

4. 5,6,7,8-四氢-2H-环庚[c]吡啶-3,9-二酮的合成4. Synthesis of 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione

在140℃下将3,9-二氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-4-甲腈(17.0g,0.084mol)于50％浓硫酸(100mL)中的溶液搅拌12h。在0℃下将反应混合物用50％氢氧化钠缓慢中和至pH 7-8。在减压下移除水。将残余物溶解至温氯仿中并通过过滤移除不溶性固体。将滤液浓缩并通过硅胶柱色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的5,6,7,8-四氢-2H-环庚[c]吡啶-3,9-二酮(9.5g，产率63％)。ESI-MS(M+H)+:178.1。A solution of 3,9-dioxo-3,5,6,7,8,9-hexahydro-2H-cycloheptyl [c] pyridine-4-carbonitrile (17.0 g, 0.084 mol) in 50% concentrated sulfuric acid (100 mL) was stirred for 12 h at 140 ° C. The reaction mixture was slowly neutralized to pH 7-8 with 50% sodium hydroxide at 0 ° C. Water was removed under reduced pressure. The residue was dissolved in warm chloroform and insoluble solids were removed by filtration. The filtrate was concentrated and purified by silica gel column chromatography (DCM/MeOH=20:1) to obtain 5,6,7,8-tetrahydro-2H-cycloheptyl [c] pyridine-3,9-dione (9.5 g, yield 63%) as a yellow solid. ESI-MS (M+H) + : 178.1.

5. 9-氨基-2,5,6,7,8,9-六氢-3H-环庚[c]吡啶-3-酮的合成5. Synthesis of 9-amino-2,5,6,7,8,9-hexahydro-3H-cyclohepta[c]pyridin-3-one

将5,6,7,8-四氢-2H-环庚[c]吡啶-3,9-二酮(7.0g,39.5mmol)、NH4OAc(60.8g,790.0mmol)和NaBH3CN(7.4g,118.5mmol)于i-PrOH(150mL)中的混合物在80℃下加热8h并冷却至室温。将溶液用于下一步骤而无需纯化。ESI-MS(M+H)+:179.2。A mixture of 5,6,7,8-tetrahydro-2H-cyclohepta[c]pyridine-3,9-dione (7.0 g, 39.5 mmol), NH 4 OAc (60.8 g, 790.0 mmol) and NaBH 3 CN (7.4 g, 118.5 mmol) in i-PrOH (150 mL) was heated at 80° C. for 8 h and cooled to room temperature. The solution was used in the next step without purification. ESI-MS (M+H) + : 179.2.

6.(3-氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成6. Synthesis of tert-butyl (3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate

向先前溶液中添加NaHCO3(水性，50mL)、THF(50mL)和Boc2O(17.2g,79.0mmol)。在室温下将混合物搅拌6h。浓缩并用水(100mL)稀释之后，用DCM(3×200mL)萃取混合物。将合并的有机层用盐水(200mL)洗涤，干燥(Na2SO4)，过滤并浓缩。将粗产物通过硅胶柱色谱法(DCM/MeOH＝20:1)纯化，以得到呈黄色固体的(3-氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(6.2g，产率：56％(两个步骤))。ESI-MS(M+H)+:279.2。1H NMR(400MHz,CDCl3)δ:7.25(s,1H),6.35(s,1H),5.30(brs,1H),2.65-2.63(m,2H),1.86-1.76(m,4H),1.45(s,9H),1.39-1.35(m,2H)。NaHCO 3 (aqueous, 50 mL), THF (50 mL) and Boc 2 O (17.2 g, 79.0 mmol) were added to the previous solution. The mixture was stirred at room temperature for 6 h. After concentration and dilution with water (100 mL), the mixture was extracted with DCM (3×200 mL). The combined organic layer was washed with brine (200 mL), dried (Na 2 SO 4 ), filtered and concentrated. The crude product was purified by silica gel column chromatography (DCM/MeOH=20:1) to obtain tert-butyl (3-oxo-3,5,6,7,8,9-hexahydro-2H-cycloheptyl [c] pyridin-9-yl)carbamate (6.2 g, yield: 56% (two steps)) as a yellow solid. ESI-MS (M+H) + : 279.2. 1 H NMR (400MHz, CDCl 3 ) δ: 7.25 (s, 1H), 6.35 (s, 1H), 5.30 (brs, 1H), 2.65-2.63 (m, 2H), 1.86-1.76 (m, 4H), 1.45 (s, 9H), 1.39-1.35 (m, 2H).

7.三氟甲烷磺酸9-((叔丁氧基羰基)氨基)-6,7,8,9-四氢-5H-环庚[c]吡啶-3-基酯的合成7. Synthesis of 9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cycloheptyl[c]pyridin-3-yl trifluoromethanesulfonate

在0℃下向(3-氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(6.2g,22.3mmol)和三乙胺(6.8g,66.9mmol)于DCM(150mL)中的溶液中逐滴添加Tf2O(9.4g,33.5mmol)。将混合物搅拌1小时。将溶液用水(150mL)稀释，用DCM(2×200mL)萃取。将合并的有机层用盐水洗涤，经Na2SO4干燥，过滤并浓缩。将粗产物通过硅胶柱色谱法(石油醚/EtOAc＝4:1)纯化，以得到呈黄色固体的9-((叔丁氧基羰基)氨基)-6,7,8,9-四氢-5H-环庚[c]吡啶-3-基三氟甲烷磺酸酯(5.7g，Y：63％)。ESI-MS(M+H)+:411.1。To a solution of tert-butyl (3-oxo-3,5,6,7,8,9-hexahydro-2H-cyclohepta[c]pyridin-9-yl)carbamate (6.2 g, 22.3 mmol) and triethylamine (6.8 g, 66.9 mmol) in DCM (150 mL) was added Tf 2 O (9.4 g, 33.5 mmol) dropwise at 0° C. The mixture was stirred for 1 hour. The solution was diluted with water (150 mL), extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give 9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yl trifluoromethanesulfonate (5.7 g, Y: 63%) as a yellow solid. ESI-MS (M+H) + :411.1.

8.(3-(1-乙氧基乙烯基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成8. Synthesis of tert-butyl (3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[c]pyridin-9-yl)carbamate

在70℃、氮气下将三氟甲烷磺酸9-((叔丁氧基羰基)氨基)-6,7,8,9-四氢-5H-环庚[c]吡啶-3-基酯(2.4g,5.85mmol)、三丁基(1-乙氧基乙烯基)锡烷(4.3g,11.7mmol)、三乙胺(1.8g,17.6mmol)、Pd(OAc)2(131mg,0.58mmol)和dppp(903mg,2.34mmol)于50mL DMF中的混合物在密封管中搅拌2h。将混合物用EtOAc(200mL)稀释并用水(3×100mL)洗涤。将有机相用Na2SO4干燥并浓缩。将粗产物通过硅胶柱色谱法(石油醚/EtOAc＝4:1)纯化，以得到呈黄色固体的(3-(1-乙氧基乙烯基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(1.0g，产率：51％)。ESI-MS(M+H)+:333.2。A mixture of 9-((tert-butoxycarbonyl)amino)-6,7,8,9-tetrahydro-5H-cyclohept[c]pyridin-3-yl trifluoromethanesulfonate (2.4 g, 5.85 mmol), tributyl(1-ethoxyvinyl)stannane (4.3 g, 11.7 mmol), triethylamine (1.8 g, 17.6 mmol), Pd(OAc) 2 (131 mg, 0.58 mmol) and dppp (903 mg, 2.34 mmol) in 50 mL DMF was stirred in a sealed tube at 70° C. under nitrogen for 2 h. The mixture was diluted with EtOAc (200 mL) and washed with water (3×100 mL). The organic phase was dried over Na 2 SO 4 and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give tert-butyl (3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (1.0 g, yield: 51%) as a yellow solid. ESI-MS (M+H) + : 333.2.

9. 1-(9-氨基-6,7,8,9-四氢-5H-环庚[c]吡啶-3-基)乙-1-酮的合成9. Synthesis of 1-(9-amino-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-3-yl)ethan-1-one

向(3-(1-乙氧基乙烯基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(1.0g,3.0mmol)于THF(30mL)中的溶液中逐滴添加HCl(1mL,6.0mmol)。在室温下将混合物搅拌1h。将溶液用于下一步骤而无需纯化。ESI-MS(M+H)+:205.1。To a solution of tert-butyl (3-(1-ethoxyvinyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[c]pyridin-9-yl)carbamate (1.0 g, 3.0 mmol) in THF (30 mL) was added HCl (1 mL, 6.0 mmol) dropwise. The mixture was stirred at room temperature for 1 h. The solution was used in the next step without purification. ESI-MS (M+H) + : 205.1.

10.(3-乙酰基-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成10. Synthesis of tert-butyl (3-acetyl-6,7,8,9-tetrahydro-5H-cycloheptyl[c]pyridin-9-yl)carbamate

(3-乙酰基-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成类似于(3-氧代-3,5,6,7,8,9-六氢-2H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成(实施例40，步骤6)。将粗产物通过硅胶柱色谱法(石油醚/EtOAc＝4:1)纯化，以得到呈黄色固体的(3-乙酰基-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(550mg，产率：60％(两个步骤))。ESI-MS(M+H)+:305.2。1H NMR(400MHz,CDCl3)δ:8.54(s,1H),7.78(s,1H),4.99-4.97(m,2H),2.91-2.90(m,2H),2.70(s,3H),1.94-1.74(m,4H),1.62-1.60(m,2H),1.45(s,9H)。The synthesis of tert-butyl (3-acetyl-6,7,8,9-tetrahydro-5H-cycloheptyl [c] pyridin-9-yl) carbamate is similar to the synthesis of tert-butyl (3-oxo-3,5,6,7,8,9-hexahydro-2H-cycloheptyl [c] pyridin-9-yl) carbamate (Example 40, Step 6). The crude product was purified by silica gel column chromatography (petroleum ether/EtOAc=4:1) to give tert-butyl (3-acetyl-6,7,8,9-tetrahydro-5H-cycloheptyl [c] pyridin-9-yl) carbamate (550 mg, yield: 60% (two steps)) as a yellow solid. ESI-MS (M+H) + : 305.2. 1 H NMR (400MHz, CDCl 3 )δ:8.54(s,1H),7.78(s,1H),4.99-4.97(m,2H),2.91-2.90(m,2H),2.70(s,3H),1.94-1.74(m,4H),1.62-1.60(m,2H),1.45(s,9 H).

11.(3-(3-(二甲基氨基)丙烯酰基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成11. Synthesis of tert-butyl (3-(3-(dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

在100℃下将(3-乙酰基-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(550mg,1.8mmol)于DMF-DMA(10mL)中的溶液搅拌2h。浓缩之后，将粗产物通过反相HPLC(CH3CN/0.05％于水中的NH3.H2O)纯化，以得到(3-(3-(二甲基氨基)丙烯酰基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(380mg，产率：61％)。ESI-MS(M+H)+:360.2。A solution of tert-butyl (3-acetyl-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (550 mg, 1.8 mmol) in DMF-DMA (10 mL) was stirred at 100° C. for 2 h. After concentration, the crude product was purified by reverse phase HPLC (CH 3 CN/0.05% NH 3 .H 2 O in water) to give tert-butyl (3-(3-(dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (380 mg, yield: 61%). ESI-MS (M+H) + : 360.2.

12. 1-(1-甲基-1H-吡唑-4-基)胍盐酸盐12. 1-(1-Methyl-1H-pyrazol-4-yl)guanidine hydrochloride

向1-甲基-1H-吡唑-4-胺(500mg,5mmol,1.0当量)于二噁烷(10mL)中的溶液中添加氰胺(273g,6.5mmol,1.3当量)和浓HCl(1mL)。在100℃下将反应物搅拌12h。在减压下移除溶剂。将残余物从MeOH和Et2O的共溶剂再结晶。获得呈黄色固体的1-(1-甲基-1H-吡唑-4-基)胍盐酸盐(600mg，产率：55％)。ESI-MS(M+H)+:140.1。1H NMR(400MHz,CD3OD)δ:7.78(s,1H),7.48(s,1H),3.91(s,3H)。To a solution of 1-methyl-1H-pyrazol-4-amine (500 mg, 5 mmol, 1.0 eq.) in dioxane (10 mL) was added cyanamide (273 g, 6.5 mmol, 1.3 eq.) and concentrated HCl (1 mL). The reaction was stirred at 100 °C for 12 h. The solvent was removed under reduced pressure. The residue was recrystallized from a co-solvent of MeOH and Et 2 O. 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride (600 mg, yield: 55%) was obtained as a yellow solid. ESI-MS (M+H) + : 140.1. 1 H NMR (400 MHz, CD 3 OD) δ: 7.78 (s, 1H), 7.48 (s, 1H), 3.91 (s, 3H).

13.(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成13. Synthesis of tert-butyl (3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

将1-(1-甲基-1H-吡唑-4-基)胍盐酸盐(588mg,4.23mmol)、K2CO3(1.2g,8.46mmol)和三乙胺(855mg,8.46mmol)于EtOH(10mL)中的混合物在室温下搅拌1h，然后添加(3-(3-(二甲基氨基)丙烯酰基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(380mg,1.06mmol)，并且将混合物加热至90℃持续12h。浓缩之后，将粗产物通过反相HPLC(CH3CN/0.05％于水中的NH3.H2O)纯化，以得到(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(240mg，产率：52％)。ESI-MS(M+H)+:436.2。1H NMR(400MHz,CDCl3)δ:8.57(s,1H),8.50(d,J＝5.2Hz,1H),8.08(s,1H),7.85(s,1H),7.66(d,J＝5.6Hz,1H),7.60(s,1H),6.92(s,1H),5.00(br,2H),3.92(s,3H),2.97-2.90(m,2H),2.01-1.82(m,5H),1.51-1.46(m,10H)。A mixture of 1-(1-methyl-1H-pyrazol-4-yl)guanidine hydrochloride (588 mg, 4.23 mmol ) , K2CO3 (1.2 g, 8.46 mmol) and triethylamine (855 mg, 8.46 mmol) in EtOH (10 mL) was stirred at room temperature for 1 h, then tert-butyl (3-(3-(dimethylamino)acryloyl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (380 mg, 1.06 mmol) was added and the mixture was heated to 90 °C for 12 h. After concentration, the crude product was purified by reverse phase HPLC ( CH3CN / 0.05% NH3.H2O in water) to give tert-butyl (3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (240 mg, yield: 52%). ESI-MS (M+H) + : 436.2. 1 H NMR (400MHz, CDCl 3 ) δ: 8.57 (s, 1H), 8.50 (d, J = 5.2Hz, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.66 (d, J = 5.6Hz, 1H), 7.60 (s, 1H), 6.92 (s, 1H), 5.00 (br, 2H), 3 .92(s,3H),2.97-2.90(m,2H),2.01-1.82(m,5H),1.51-1.46(m,10H).

14. 3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-胺的合成14. Synthesis of 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine

向(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(240mg,0.55mmol)于DCM(5mL)中的溶液中添加TFA(5mL)。在室温下将混合物搅拌1h。浓缩之后，将残余物用NaHCO3(水溶液)酸化并用DCM(3×30mL)萃取，干燥并浓缩，以得到呈黄色固体的3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-胺(170mg，Y：92％，用于下一步骤而无需进一步纯化)。ESI-MS(M+H)+:336.2。To a solution of tert-butyl (3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (240 mg, 0.55 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 1 h. After concentration, the residue was acidified with NaHCO 3 (aq) and extracted with DCM (3×30 mL), dried and concentrated to give 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine (170 mg, Y: 92%, used in the next step without further purification) as a yellow solid. ESI-MS (M+H) + : 336.2.

15. 5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺(I-IM_29)的合成15. Synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (I-IM_29)

向3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-胺(80mg,0.24mmol)和三乙胺(49mg,0.48mmol)于DCM(5mL)中的溶液中添加HATU(182mg,0.48mmol)和5-(叔丁基)-1,3,4-噁二唑-2-羧酸钾(75mg,0.36mmol)。在室温下将混合物搅拌3h。然后添加水(30mL)并用DCM(2×50mL)萃取混合物。将合并的有机物干燥并浓缩。将粗产物通过硅胶柱色谱法(DCM/MeOH＝10:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺(60mg，产率：51％)。ESI-MS(M+H)+:487.9。1H NMR(400MHz,CD3OD)δ:8.52(s,1H),8.49(d,J＝5.2Hz,1H),8.22(s,1H),7.97(s,1H),7.66(s,1H),7.54(d,J＝5.2Hz,1H),5.47-5.45(m,1H),3.90(s,3H),3.08-3.06(m,2H),2.13-1.98(m,5H),1.51-1.49(m,10H)。To a solution of 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine (80 mg, 0.24 mmol) and triethylamine (49 mg, 0.48 mmol) in DCM (5 mL) was added HATU (182 mg, 0.48 mmol) and potassium 5-(tert-butyl)-1,3,4-oxadiazole-2-carboxylate (75 mg, 0.36 mmol). The mixture was stirred at room temperature for 3 h. Water (30 mL) was then added and the mixture was extracted with DCM (2×50 mL). The combined organics were dried and concentrated. The crude product was purified by silica gel column chromatography (DCM/MeOH=10:1) to give 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (60 mg, yield: 51%) as a yellow solid. ESI-MS (M+H) + : 487.9. 1 H NMR (400MHz, CD 3 OD) δ: 8.52 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.54 (d, J = 5.2Hz, 1H), 5.47-5.45 (m, 1H), 3.90 (s ,3H),3.08-3.06(m,2H),2.13-1.98(m,5H),1.51-1.49(m,10H).

实施例41：(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺(化合物41)Example 41: (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (Compound 41)

使5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺(216mg,0.44mmol)经历手性SFC分离(CHIRALPAK AS-H 30×250mm，5um；共溶剂：20％甲醇+0.1％DEA于CO2中(流率：100g/min)；系统背压：120巴)，以得到呈白色固体的(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺(93mg，产率：43％)。ESI-MS(M+H)+:488.1。1H NMR(400MHz,CD3OD)δ:ppm8.52(s,1H),8.49(d,J＝5.1Hz,1H),8.22(s,1H),7.97(s,1H),7.65(s,1H),7.55(d,J＝5.0Hz,1H),5.46(brd,J＝9.5Hz,1H),3.90(s,3H),3.07(br t,J＝4.4Hz,2H),2.12(br d,J＝8.8Hz,2H),1.91-2.05(m,3H),1.44-1.57(m,10H)。5-(tert-Butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (216 mg, 0.44 mmol) was subjected to chiral SFC separation (CHIRALPAK AS-H 30×250 mm, 5 um; co-solvent: 20% methanol + 0.1% DEA in CO 2 (flow rate: 100 g/min; system back pressure: 120 bar) to give (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (93 mg, yield: 43%) as a white solid. ESI-MS (M+H) + : 488.1. 1 H NMR (400MHz, CD 3 OD) δ: ppm8.52 (s, 1H), 8.49 (d, J = 5.1Hz, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.55 (d, J = 5.0Hz, 1H), 5.46 (brd, J = 9.5Hz, 1H), 3.9 0(s,3H),3.07(br t,J＝4.4Hz,2H),2.12(br d,J＝8.8Hz,2H),1.91-2.05(m,3H),1.44-1.57(m,10H).

实施例42：(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(化合物42a)和(S)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(化合物42b)Example 42: (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 42a) and (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 42b)

1. 5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺的合成1. Synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide

5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺的合成类似于5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺的合成(实施例40，步骤15)。将滤液通过硅胶柱色谱法(DCM/MeOH＝10:1)纯化，以得到呈黄色固体的5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(55mg，产率：47％)。ESI-MS(M+H)+:487.9。1H NMR(400MHz,CD3OD)δ:8.50(s,1H),8.49(d,J＝5.6Hz,1H),8.21(s,1H),7.97(s,1H),7.66(s,1H),7.54(d,J＝5.2Hz,1H),5.49-5.47(m,1H),3.90(s,3H),3.08-3.06(m,2H),2.12-1.97(m,5H),1.52-1.50(m,10H)。The synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide was similar to the synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide (Example 40, Step 15). The filtrate was purified by silica gel column chromatography (DCM/MeOH=10:1) to give 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (55 mg, yield: 47%) as a yellow solid. ESI-MS (M+H) + : 487.9. 1 H NMR (400MHz, CD 3 OD) δ: 8.50 (s, 1H), 8.49 (d, J = 5.6Hz, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.54 (d, J = 5.2Hz, 1H), 5.49-5.47 (m, 1H), 3.90 (s ,3H),3.08-3.06(m,2H),2.12-1.97(m,5H),1.52-1.50(m,10H).

2.(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(I-IM_31)和(S)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(化合物42)的合成2. Synthesis of (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (I-IM_31) and (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (Compound 42)

使5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(40mg,0.08mmol)经历手性SFC分离(CHIRALPAK AS-H 30×250mm，5um；共溶剂：30％甲醇+0.1％DEA于CO2中(流率：100g/min)；系统背压：120巴)，以得到呈白色固体的(R)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(11mg，产率：27％)和(S)-5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,2,4-噁二唑-3-甲酰胺(10mg,26％)。5-(tert-Butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (40 mg, 0.08 mmol) was subjected to chiral SFC separation (CHIRALPAK AS-H 30×250 mm, 5 um; co-solvent: 30% methanol + 0.1% DEA in CO (flow rate: 100 g/min); system back pressure: 120 bar) to give (R)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide as a white solid. The mixture was mixed with (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (11 mg, yield: 27%) and (S)-5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,2,4-oxadiazole-3-carboxamide (10 mg, 26%).

(R):ESI-MS(M+H)+:488.1。1H NMR(400MHz,CD3OD)δ:8.51(s,1H),8.49(s,1H),8.22(s,1H),7.97(s,1H),7.65(s,1H),7.55(d,J＝5.1Hz,1H),5.48(br d,J＝9.3Hz,1H),3.90(s,3H),3.01-3.11(m,2H),1.90-2.14(m,5H),1.50-1.53(m,9H)。(R):ESI-MS(M+H) + :488.1. 1 H NMR (400MHz, CD 3 OD) δ: 8.51 (s, 1H), 8.49 (s, 1H), 8.22 (s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.55 (d ,J＝5.1Hz,1H),5.48(br d,J＝9.3Hz,1H),3.90(s,3H),3.01-3.11(m,2H),1.90-2.14(m,5H),1.50-1.53 (m,9H).

(S):ESI-MS(M+H)+:488.1。1H NMR(400MHz,CD3OD)δ:8.50-8.51(m,1H),8.48(s,1H),8.21(s,1H),7.96(s,1H),7.65(s,1H),7.53-7.56(m,1H),5.47(br d,J＝9.5Hz,1H),3.89(s,3H),3.02-3.13(m,2H),1.91-2.16(m,5H),1.50-1.52(m,10H)。(S):ESI-MS(M+H) + :488.1. 1 H NMR (400MHz, CD 3 OD) δ:8.50-8.51(m,1H),8.48(s,1H),8.21(s,1H),7.96(s,1H),7.65(s,1H),7.53 -7.56(m,1H),5.47(br d,J＝9.5Hz,1H),3.89(s,3H),3.02-3.13(m,2H),1.91-2.16(m,5H),1.50-1.52( m,10H).

实施例43. 1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺(化合物43)Example 43. 1-(tert-Butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide (Compound 43)

1.(3-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成1. Synthesis of tert-butyl (3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

(3-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成类似于1-(5-(叔丁基)-1,2,4-噁二唑-3-甲酰氨基)-7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-4,5-二氢-1H-苯并[d]氮杂-3(2H)-羧酸叔丁酯的合成(实施例1，步骤12)。将粗产物通过硅胶色谱法(石油醚/EtOAc＝3:1)纯化，以得到呈黄色固体的(3-(2-氯吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(170mg，产率：42％)。ESI-MS(M+H)+:374.2。The synthesis of tert-butyl (3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate was similar to that of 1-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-4,5-dihydro-1H-benzo[d]azepine -Synthesis of tert-butyl 3(2H)-carboxylate (Example 1, Step 12). The crude product was purified by silica gel chromatography (petroleum ether/EtOAc=3:1) to give tert-butyl (3-(2-chloropyridin-4-yl)-6,7,8,9-tetrahydro-5H-cycloheptyl[c]pyridin-9-yl)carbamate (170 mg, yield: 42%) as a yellow solid. ESI-MS (M+H) + : 374.2.

2.(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成2. Synthesis of tert-butyl (3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate

(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯的合成类似于(R)-(2-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-苯并[7]轮烯-5-基)氨基甲酸叔丁酯的合成(实施例35，步骤2)。将粗产物通过硅胶柱色谱法(PE/EtOAc＝1:1)纯化，以得到呈黄色固体的(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)氨基甲酸叔丁酯(140mg,Y:71％)。ESI-MS(M+H)+:435.2。The synthesis of tert-butyl (3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate was similar to the synthesis of tert-butyl (R)-(2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (Example 35, Step 2). The crude product was purified by silica gel column chromatography (PE/EtOAc=1:1) to give tert-butyl (3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)carbamate (140 mg, Y: 71%) as a yellow solid. ESI-MS (M+H) + : 435.2.

3. 3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-胺的合成3. Synthesis of 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine

3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-胺的合成类似于5-(叔丁基)-N-(7-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-2,3,4,5-四氢-1H-苯并[d]氮杂-1-基)-1,2,4-噁二唑-3-甲酰胺的合成(实施例1，步骤13)。获得呈黄色固体的粗产物3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-胺(100mg，产率：94％)。ESI-MS(M+H)+:335.2。The synthesis of 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine was similar to that of 5-(tert-butyl)-N-(7-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine -1-yl)-1,2,4-oxadiazole-3-carboxamide (Example 1, Step 13). The crude product 3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-amine (100 mg, yield: 94%) was obtained as a yellow solid. ESI-MS (M+H) + : 335.2.

4. 1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺的合成4. Synthesis of 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide

1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺的合成类似于实施例40步骤15中5-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)嘧啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1,3,4-噁二唑-2-甲酰胺的合成。将粗产物通过硅胶色谱法(DCM/MeOH＝15:1)纯化，以得到呈黄色固体的1-(叔丁基)-N-(3-(2-((1-甲基-1H-吡唑-4-基)氨基)吡啶-4-基)-6,7,8,9-四氢-5H-环庚[c]吡啶-9-基)-1H-1,2,3-三唑-4-甲酰胺(46mg，产率：32％)。ESI-MS(M+H)+:486.3。1H NMR(400MHz,CD3OD)δ:8.53-8.49(m,2H),8.16(d,J＝5.2Hz,1H),7.92(s,1H),7.69(s,1H),7.51(s,1H),7.20-7.17(m,2H),5.45-5.43(m,1H),3.89(s,3H),3.08-3.06(m,2H),2.14-2.00(m,5H),1.74(s,9H),1.59-1.50(m,1H)。The synthesis of 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide was similar to the synthesis of 5-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1,3,4-oxadiazole-2-carboxamide in step 15 of Example 40. The crude product was purified by silica gel chromatography (DCM/MeOH=15:1) to give 1-(tert-butyl)-N-(3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridin-9-yl)-1H-1,2,3-triazole-4-carboxamide (46 mg, yield: 32%) as a yellow solid. ESI-MS (M+H) + : 486.3. 1 H NMR (400MHz, CD 3 OD) δ: 8.53-8.49 (m, 2H), 8.16 (d, J = 5.2Hz, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 7.20-7.17 (m, 2H), 5.45-5.43 (m, 1H), 3.89 (s,3H),3.08-3.06(m,2H),2.14-2.00(m,5H),1.74(s,9H),1.59-1.50(m,1H).

实施例44-154.Examples 44-154.

以下化合物为根据与实施例1-43中所述的程序类似的程序合成。The following compounds were synthesized according to procedures similar to those described in Examples 1-43.

*指示在手性中心的立体化学为任意指定的。*Indicates that the stereochemistry at a chiral center is arbitrarily assigned.

**指示外消旋混合物的两个手性中心的相对立体化学为任意指定的，即一个手性中心相对于另一手性中心的反式或顺式组态为任意指定的。**Indicates that the relative stereochemistry of the two chiral centers of a racemic mixture is arbitrarily assigned, ie, the trans or cis configuration of one chiral center relative to the other chiral center is arbitrarily assigned.

实施例155.体外BTK激酶测定：BTK-POLYGAT-LS测定Example 155. In vitro BTK kinase assay: BTK-POLYGAT-LS assay

BTK体外测定的目的为通过测量IC50来确定对BTK的化合物效能。在活性BTK酶(Upstate 14-552)、ATP和抑制剂存在下监测荧光素标记的聚GAT肽(Invitrogen PV3611)的磷酸化的量之后测量化合物抑制。在黑色96孔板(costar 3694)中进行BTK激酶反应。对于典型的测定，向每个孔中添加24pL的ATP/肽主要混合物(最终浓度；ATP10μΜ，聚GAT100nM)于激酶缓冲液(10mM Tris-HCl pH 7.5、10mM MgCl2、200μΜNa3PO4、5mM DTT、0.01％Triton X-100和0.2mg/ml酪蛋白)中的等分试样。接着，添加I pL于100％DMSO溶剂中的4倍40X化合物滴定，接着添加15uL于1X激酶缓冲液(具有最终浓度0.25nM)中的BTK酶。将测定物孵育30分钟，之后用28pL 50mM EDTA溶液停止。将激酶反应物的等分试样(5uL)转移至小体积白色384孔板(Coming 3674)中，并添加5pL 2X检测缓冲液(Invitrogen PV3574，具有4nM Tb-PY20抗体，Invitrogen PV3552)。将板覆盖并在室温下孵育45分钟。在MolecularDevices M5(332nm激发；488nm发射；518nm荧光素发射)上测量时间分辨荧光(TRF)。使用四参数拟合用由DMSO对照确定的100％酶活性和由EDTA对照确定的0％活性计算IC50值。The purpose of the BTK in vitro assay is to determine the compound potency against BTK by measuring IC 50. Compound inhibition is measured after monitoring the amount of phosphorylation of fluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP and inhibitor. BTK kinase reactions are performed in black 96-well plates (costar 3694). For a typical assay, 24 pL of ATP/peptide master mix (final concentration; ATP 10 μM, polyGAT 100 nM) in kinase buffer (10 mM Tris-HCl pH 7.5, 10 mM MgCl2, 200 μM Na 3 PO 4 , 5 mM DTT, 0.01% Triton X-100 and 0.2 mg/ml casein) is added to each well. Next, 1 pL of 4 times 40X compound titration in 100% DMSO solvent was added, followed by 15uL of BTK enzyme in 1X kinase buffer (with a final concentration of 0.25nM). The assay was incubated for 30 minutes, followed by 28pL of 50mM EDTA solution. An aliquot (5uL) of the kinase reaction was transferred to a small volume white 384-well plate (Corning 3674), and 5pL of 2X detection buffer (Invitrogen PV3574, with 4nM Tb-PY20 antibody, Invitrogen PV3552) was added. The plate was covered and incubated at room temperature for 45 minutes. Time-resolved fluorescence (TRF) was measured on Molecular Devices M5 (332nm excitation; 488nm emission; 518nm fluorescein emission). IC 50 values were calculated using a four-parameter fit with 100% enzyme activity determined by the DMSO control and 0% activity determined by the EDTA control.

表1显示体外Btk激酶测定中选择的本发明化合物的活性，其中每个化合物编号对应于本文实施例1-154中所列出的化合物编号。表示IC50等于或小于1000nM且大于10nM；表示IC50等于或小于10nM且大于1nM；并且表示IC50等于或小于1nM。Table 1 shows the activity of selected compounds of the invention in an in vitro Btk kinase assay, wherein each compound number corresponds to the compound number listed in Examples 1-154 herein. Indicates that the IC 50 is equal to or less than 1000 nM and greater than 10 nM; Means that the IC50 is equal to or less than 10 nM and greater than 1 nM; and Indicates that the IC50 is equal to or less than 1 nM.

表1.Table 1.

实施例156.人全血中的体外PD测定Example 156. In vitro PD assay in human whole blood

人肝素化静脉血购自Bioreclamation,Inc.或SeraCare Life Sciences并运送过夜。将全血等分至96孔板中并“掺”有测试化合物于DMSO中的连续稀释液或有不含药物的DMSO。所有孔中DMSO的最终浓度为0.1％。将板在37℃下孵育30min。将含有蛋白酶和磷酸酶抑制剂的裂解缓冲液添加至含药物的样品和一个仅DMSO样品(+PPi，高对照)中，同时将含有蛋白酶抑制剂的裂解缓冲液添加至其他仅DMSO样品(-PPi，低对照)中。使所有裂解的全血样品经历US20160311802中所述的总BTK捕获和磷酸酪氨酸检测方法，所述专利以引用的方式并入本文。在Prism中对ECL值作图，并且将具有通过+PPi高和-PPi低对照所限定的最大值和最小值的限制的最佳拟合曲线用于通过内推来估计导致50％ECL信号抑制的测试化合物浓度。Human heparinized venous blood was purchased from Bioreclamation, Inc. or SeraCare Life Sciences and shipped overnight. Whole blood was aliquoted into 96-well plates and "doped" with serial dilutions of test compounds in DMSO or with drug-free DMSO. The final concentration of DMSO in all wells was 0.1%. The plate was incubated at 37°C for 30 min. Lysis buffer containing protease and phosphatase inhibitors was added to drug-containing samples and one DMSO-only sample (+PPi, high control), while lysis buffer containing protease inhibitors was added to other DMSO-only samples (-PPi, low control). All lysed whole blood samples were subjected to the total BTK capture and phosphotyrosine detection method described in US20160311802, which is incorporated herein by reference. ECL values were plotted in Prism, and the best fit curve with the maximum and minimum limits defined by +PPi high and -PPi low controls was used to estimate the test compound concentration that resulted in 50% ECL signal inhibition by interpolation.

表2显示pBTK测定中选择的本发明化合物的活性，其中每个化合物编号对应于本文所述的实施例1-154中所述的化合物编号。表示IC50等于或小于10,000nM但大于500nM，表示IC50等于或小于500nM但大于100nM；并且表示IC50等于或小于100nM。Table 2 shows the activity of selected compounds of the invention in the pBTK assay, wherein each compound number corresponds to the compound number described in Examples 1-154 described herein. Means that the IC50 is equal to or less than 10,000nM but greater than 500nM, means that the IC50 is equal to or less than 500 nM but greater than 100 nM; and Indicates that the IC50 is equal to or less than 100 nM.

表2Table 2

Claims (38)

1. A compound represented by the formula:
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the formula:
or a pharmaceutically acceptable salt thereof.
3. (R) -1- (tert-butyl) -N- (8- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2- (oxetan-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c)]Aza-compoundsCrystalline form a of-5-yl) -1H-1,2, 3-triazole-4-carboxamide, characterized by at least three powder X-ray diffraction (PXRD) peaks at 2Θ angles selected from: 5.7 °, 7.9 °, 9.7 °, 18.2 °, 19.0 °, and 22.4 °, wherein form a is a hydrate.
4. Form a of claim 3, wherein the form is characterized by at least four PXRD peaks at 2Θ angles selected from: 5.7 °, 7.9 °, 9.7 °, 18.2 °, 19.0 °, and 22.4 °.
5. Form a of claim 3, wherein the form is characterized by at least five PXRD peaks at 2Θ angles selected from: 5.7 °, 7.9 °, 9.7 °, 18.2 °, 19.0 °, and 22.4 °.
6. Form a of claim 3, wherein the form is characterized by PXRD peaks at 2Θ angles selected from: 5.7 °, 7.9 °, 9.7 °, 18.2 °, 19.0 °, and 22.4 °.
7. Form a of claim 3, wherein the form is characterized by PXRD peaks at 2Θ angles selected from: 4.3 °, 5.7 °, 7.9 °, 8.7 °, 9.7 °, 11.9 °, 13.1 °, 14.8 °, 15.2 °, 16.1 °, 17.0 °, 17.8 °, 18.2 °, 19.0 °, 20.5 °, 21.2 °, 22.4 °, 22.8 °, 23.8 °, and 25.6 °.
8. Form a of any one of claims 3 to 7, wherein the form a is characterized by a melting temperature 186.0 ℃ ± 2 ℃ as determined by Differential Scanning Calorimetry (DSC) analysis.
9. The crystalline form a of any one of claims 3 to 7, wherein the crystalline form has a DSC curve substantially the same as the DSC curve shown in figure 2.
10. The form a of any one of claims 3 to 7, wherein the form a is at least 70% pure.
11. The form a of any one of claims 3 to 7, wherein the form a is at least 80% pure.
12. The form a of any one of claims 3 to 7, wherein the form a is at least 85% pure.
13. The form a of any one of claims 3 to 7, wherein the form a is at least 90% pure.
14. The form a of any one of claims 3 to 7, wherein the form a is at least 95% pure.
15. The form a of any one of claims 3 to 7, wherein the form a is at least 97% pure.
16. The form a of any one of claims 3 to 7, wherein the form a is at least 99% pure.
17. The form a of any one of claims 3 to 7, wherein the form a is at least 99.5% pure.
18. The form a of any one of claims 3 to 7, wherein the form a is at least 99.9% pure.
19. (R) -1- (tert-butyl) -N- (8- (2- ((1-methyl-1H-pyrazol-4-yl) amino) pyrimidin-4-yl) -2- (oxetan-3-yl) -2,3,4, 5-tetrahydro-1H-benzo [ c)]Aza-compoundsCrystalline form G of-5-yl) -1H-1,2, 3-triazole-4-carboxamide characterized by at least three PXRD peaks at 2Θ angles selected from: 3.6 °, 8.9 °, 10.9 °, 12.6 °, 20.2 °, and 21.8 °.
20. The crystalline form G of claim 19, wherein the crystalline form is characterized by at least four PXRD peaks at 2Θ angles selected from: 3.6 °, 8.9 °, 10.9 °, 12.6 °, 20.2 °, and 21.8 °.
21. The crystalline form G of claim 19, wherein the crystalline form is characterized by PXRD peaks at 2Θ angles selected from: 3.6 °, 8.9 °, 10.9 °, 12.6 °, 20.2 °, and 21.8 °.
22. The crystalline form G of claim 19, wherein the crystalline form is characterized by PXRD peaks at 2Θ angles selected from: 3.6 °, 8.9 °, 10.9 °, 12.6 °, 14.5 °, 15.4 °, 16.3 °, 18.4 °, 20.2 °, 21.8 °, 23.4 °, 25.4 °, 26.8 °, and 34.2 °.
23. The crystalline form G of any one of claims 19-22, wherein the crystalline form G has a melting temperature of 217.3 ℃ ± 2 ℃ as determined by Differential Scanning Calorimetry (DSC) analysis.
24. The crystalline form G of any one of claims 19-22, wherein the crystalline form G has a DSC curve substantially the same as the DSC curve shown in figure 5.
25. The crystalline form G of any one of claims 19-22, wherein the crystalline form G is anhydrate.
26. The form G of any one of claims 19-22, wherein the form G is at least 70% pure.
27. The form G of any one of claims 19-22, wherein the form G is at least 80% pure.
28. The form G of any one of claims 19-22, wherein the form G is at least 85% pure.
29. The form G of any one of claims 19-22, wherein the form G is at least 90% pure.
30. The form G of any one of claims 19-22, wherein the form G is at least 95% pure.
31. The form G of any one of claims 19-22, wherein the form G is at least 97% pure.
32. The form G of any one of claims 19-22, wherein the form G is at least 99% pure.
33. The form G of any one of claims 19-22, wherein the form G is at least 99.5% pure.
34. The form G of any one of claims 19-22, wherein the form G is at least 99.9% pure.
35. A pharmaceutical composition comprising (i) a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof; (ii) crystalline form a of any one of claims 3-18; or (iii) the crystalline form G of any one of claims 19-34; and a pharmaceutically acceptable excipient.
36. Use of (i) a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or (ii) form a of any one of claims 3-18, or (iii) form G of any one of claims 19-34, in the manufacture of a medicament for treating a condition responsive to inhibition of bruton's tyrosine kinase in a subject.
37. The use of claim 36, wherein the disorder is an autoimmune disorder.
38. The use of claim 37, wherein the autoimmune disorder is multiple sclerosis.
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